Substituted heterocycles as c-MYC targeting agents

Abstract

Substituted heterocyclic compounds are disclosed, including substituted pyrazoles, substituted pyrimidines, and substituted triazoles. The substituted heterocycles disclosed herein are shown to be useful for the inhibition of c-MYC and can be used as therapeutic agents for the treatment of cancer and cell proliferative diseases.

Description

This application is a divisional application of Chinese patent application No. 201880099196.0, filed on August 31, 2018, entitled "Substituted Heterocycles as c-MYC Targeting Agents". Statement regarding federally sponsored research or development

[0001] This invention was made with government support under license number R01CA123484 granted by the National Institutes of Health. The government holds certain rights to this invention. background

[0002] The field of this invention relates to substituted heterocycles as c-MYC targets. In particular, the field of this invention relates to substituted pyrazoles, pyrimidines, or triazoles as c-MYC targets for the treatment of cell proliferation disorders and impairments, such as cancer.

[0003] c-MYC oncogene dysregulation plays a causal role in most human cancers, and c-MYC inhibition profoundly affects tumor growth or survival in multiple models. MYC is the most common oncogene in human cancers, overexpressed in up to half of all cancers. Therefore, developing c-MYC inhibitors is one of the most attractive potential anti-cancer strategies. Unfortunately, c-MYC is currently considered "undruggable" due to the difficulty in targeting transcription factors with small molecules. In this paper, we disclose a novel approach to targeting c-MYC and develop a series of new small-molecule inhibitors. These compounds selectively target c-MYC-driven cell proliferation and interfere with c-MYC binding to DNA. Overview

[0004] Disclosed are substituted heterocycles that can be used as c-MYC targeting agents. The substituted heterocycles may include substituted pyrazoles, substituted pyrimidines, and substituted triazoles. The disclosed heterocycles can be used in pharmaceutical compositions and methods for treating proliferative diseases such as cancer.

[0005] The disclosed substituted heterocycles may include substituted pyrazoles having formula I: in R 1 It is hydrogen, or R 1 It is an aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R1 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 2 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. R 3 It can be hydrogen, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), benzyl, hydroxyl, halogen, amide, hydrazone, carbonyl, carboxyl or alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, or R 4 It is aryl (e.g., phenyl) or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy); R 5It is an alkyl group (e.g., C1-C6 alkyl), alkoxy group (e.g., C1-C6 alkoxy), haloalkyl group (e.g., trifluoromethyl), haloalkoxy group (e.g., trifluoromethoxy), hydroxyl group or halogen; R 6 It is hydrogen, amino, alkyl, or R 6 It is aryl (e.g., phenyl) or benzyl; R 6 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy), or R 6 and R 5 Together they form a pattern The ring structure; R 7 It is hydrogen or halogen, or R 2 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 7 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. Choose any location, provided that R is the condition. 4 and R 6 At least one of them is hydrogen; Optionally, the condition is that if R 5 If it is hydrogen, then p is 1 and m is 1; and And arbitrarily, provided that if R 1 (CH2) n (X) p - is hydrogen, hydroxyl or alkyl, and R 5 If it is a hydroxyl group, then m is 1, or R 2 and R 3 At least one of them is not hydrogen.

[0006] In the disclosed formula I, Pyr is a pyrazole ring having two non-adjacent double bonds, for example, wherein the substituted pyrazole has formula I(i) or I(ii):

[0007] Specifically, the substituted pyrazole can have the formula Ia(i), Ia(ii), Ib(i), Ib(ii), Ic(i), or Ic(ii):

[0008] The disclosed compounds may exhibit one or more biological activities. The disclosed compounds may inhibit the binding of the MYC / Max complex to DNA (e.g., in a DNA gel shifting assay). The disclosed compounds may not cause significant DNA damage (e.g., at concentrations greater than about 0.001 μM, 0.005 μM, 0.01 μM, 0.1 μM, 1.0 μM, 10 μM, 100 μM or higher in an rH2AX staining assay). The disclosed compounds may inhibit the growth of cells expressing c-MYC (preferably at concentrations less than about 100 μM, 50 μM, 10 μM, 1 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, 0.001 μM or lower). The disclosed compounds do not inhibit the growth of cells that do not express c-MYC (preferably at concentrations greater than about 0.001 μM, 0.005 μM, 0.01 μM, 0.5 μM, 0.1 μM, 1.0 μM, 10 μM and 100 μM or higher).

[0009] Pharmaceutical compositions comprising the disclosed compound and suitable pharmaceutical carriers, excipients, or diluents are also disclosed. The disclosed pharmaceutical compositions may contain an effective amount of the compound for inhibiting cancer cell growth when administered to a subject in need.

[0010] Methods for treating proliferative disorders and conditions such as cancer are also disclosed. These methods may include administering the disclosed compound or a pharmaceutical composition comprising the disclosed compound to a subject in need, such as a subject suffering from cancer. The disclosed compound or a pharmaceutical composition comprising the disclosed compound may be administered, optionally in combination, with other therapeutic agents to treat proliferative disorders and conditions. Proliferative disorders and conditions treated by the disclosed methods include, but are not limited to, cancers selected from multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer. Brief description of the attached diagram

[0011] Figure 1 A computer-based screening protocol for identifying c-MYC inhibitors (in silico screen).

[0012] Figure 2The relative MYC E-box luciferase inhibitory activities of 32 compounds.

[0013] Figure 3 The selected compounds inhibited the growth of MYC WT and KO fibroblasts.

[0014] Figure 4 Cell viability after treatment with Min9 (NUCC-0176234).

[0015] Figure 5 Electrophoretic mobility shift assay (EMSA) in the presence of a 200 μM test compound.

[0016] Figure 6 (B) The relative value of DNA binding of the 200 μM test compound.

[0017] Figure 7 (C) Relationship between relative MYC / Max DNA binding and compound concentration.

[0018] Figure 8 .rH2AX assay for DNA damage.

[0019] Figure 9 In vitro metabolism of NUCC-176242 and NUCC-176248.

[0020] Figure 10 Pharmacokinetic study of NUCC-176242 in mice after IV administration of 0.5 mg / kg.

[0021] Figure 11 Myc inhibitor 361 specifically inhibits the proliferation of the Myc-dependent cell line PC3, but does not inhibit the proliferation of the Myc-independent cell line PC12.

[0022] Figure 12 Before affecting cell survival, Myc inhibitor 361 inhibits c-Myc transcriptional activity as an early event.

[0023] Figure 13 Before affecting cell survival, Myc inhibitor 361 inhibits c-Myc transcriptional activity as an early event.

[0024] Figure 14 The Myc inhibitor Min9-S1 damages the MYC transcriptional program.

[0025] Figure 15 Myc inhibitor 361 reduced tumor volume in a mouse model of prostate cancer allogeneic grafts.

[0026] Figure 16 The combination of Myc inhibitor 361 and immunotherapy significantly blocked tumor progression.

[0027] Figure 17 Myc inhibitors 975 and 031 showed significant synergistic antitumor effects with Ara-C in an AML mouse xenograft model.

[0028] Figure 18 Performance analysis of compound 201195 at a single concentration of 0.10 μM using NCI60.

[0029] Figure 19 Performance analysis of compound 200975 at a single concentration of 0.10 μM using NCI60.

[0030] Figure 20 Performance analysis of NCI60 of compound 196361 at a single concentration of 0.10 μM.

[0032] The invention is described herein using several definitions, as illustrated below and throughout this application.

[0033] Unless otherwise specified or indicated by the context, the terms “a,” “an,” and “the” mean “one or more.” For example, “a compound” should be interpreted as “one or more compounds.”

[0034] As used herein, those skilled in the art will understand that “about,” “approximately,” “substantially,” and “significantly” will vary to some extent depending on the context in which they are used. If it is not apparent to those skilled in the art that the use of these terms in a given context is appropriate, then “about” and “approximately” indicate a positive or negative margin of ≤10% for that particular term, while “substantially” and “significantly” indicate a positive or negative margin of >10% for that particular term.

[0035] As used herein, the terms “comprising” and “including” have the same meaning as the terms “containing” and “containing,” that is, these following terms are “open-ended” transitional terms that do not limit the claims solely to the elements listed following these transitional terms. The term “consisting of” is covered by the term “comprising” but should be interpreted as a “closed” transitional term that limits the claims only to the elements stated following the transitional term. The term “substantially consisting of” is covered by the term “including” but should be interpreted as a “partially closed” transitional term that allows for additional elements following the transitional term, provided that these additional elements do not substantially affect the essential and novel features of the claims.

[0036] As used in this article, “subject” can be used interchangeably with “patient” or “individual” and refers to an animal in need of treatment, which can be human or non-human.

[0037] "Subjects in need of treatment" can include subjects suffering from diseases, disorders, or conditions that respond to therapy with substituted heterocyclic compounds such as substituted pyrazoles, substituted pyrimidines, and substituted triazoles of this disclosure. For example, "subjects in need of treatment" can include subjects suffering from proliferative disorders, disorders, or conditions such as cancer (e.g., cancers such as multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer). "Subjects in need of treatment" can include subjects suffering from proliferative disorders, disorders, or conditions such as cancer that are associated with c-MYC activity and / or can be treated by administration of an effective amount of an active agent that modulates c-MYC activity.

[0038] As used herein, the term "effective amount" should refer to the dosage of a drug that provides a specific pharmacological response when administered to a large number of subjects requiring this treatment. Even if such a dosage is considered therapeutically effective by a person skilled in the art, an effective amount of a drug administered to a particular subject under specific circumstances will not always be effective in treating the condition / disease described herein.

[0039] As used herein, the term "modulation" refers to reducing or inhibiting activity and / or increasing or enhancing activity. For example, modulating c-MYC activity can mean increasing or enhancing c-MYC activity and / or decreasing or inhibiting c-MYC activity. The compounds disclosed herein can be applied to modulate c-MYC activity.

[0040] chemical entity

[0041] This document discloses novel chemical entities and their uses. The chemical entities can be described using terminology known in the art, and are discussed further below.

[0042] As used in this article, an asterisk "*" or a plus sign "+" can be used to indicate the connection point of any group or substituent.

[0043] The term “alkyl” as used in this article includes all its isomers, including straight-chain or branched alkyl groups, such as straight-chain or branched groups with 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively.

[0044] The term "alkylene" refers to a dimethyl group of an alkyl group (e.g., -(CH2)). n - where n is an integer, such as an integer between 1 and 20). An exemplary alkylene group is -CH2CH2-.

[0045] The term "halogenated alkyl" refers to an alkyl group that has been substituted with at least one halogen. Examples include -CH2F, -CHF2, -CF3, -CH2CF3, and -CF2CF3.

[0046] As used herein, the term "heteroalkyl" refers to an "alkyl" in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). One type of heteroalkyl is an "alkoxy".

[0047] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight-chain or branched group with 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively.

[0048] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight-chain or branched group with 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkynyl, C2-C10-alkynyl, and C2-C6-alkynyl, respectively.

[0049] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon group having 3-12, 3-8, 4-8, or 4-6 carbon atoms, for example, referred to herein as "C4-8-cycloalkyl," which is derived from cycloalkanes. Unless otherwise stated, the cycloalkyl group is optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidyl, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate, phosphonate, phosphonite, sulfate, sulfide, sulfonylamino, sulfonyl, or thiocarbonyl. In some embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted.

[0050] The term "cyclohexaalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic hydrocarbon group with 3-12, 3-8, 4-8, or 4-6 carbons, wherein at least one carbon of the cycloalkane is replaced by a heteroatom such as N, O, and / or S.

[0051] The term "cycloolefin" refers to a cycloalkyl group that is additionally unsaturated on one or more ring bonds.

[0052] The term "partially unsaturated carbocyclic group" refers to a monovalent cyclic hydrocarbon containing at least one double bond between ring atoms, wherein at least one ring of the carbocyclic group is not aromatic. Partially unsaturated carbocyclic groups can be characterized according to the number of ring carbon atoms. For example, a partially unsaturated carbocyclic group may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and is thus referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclic group, respectively. Partially unsaturated carbocyclic groups can be in the form of monocyclic, bicyclic, tricyclic, bridged, spirocyclic, or other carbocyclic systems. Exemplary partially unsaturated carbocyclic groups include partially unsaturated cycloalkenyl and bicyclic carbocyclic groups. Unless otherwise stated, the partially unsaturated carbocyclic group is optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidine, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydroxyl, imino, ketone, nitro, phosphate, phosphonate, phosphonite, sulfate, sulfide, sulfonylamino, sulfonyl, or thiocarbonyl. In some embodiments, the partially unsaturated carbocyclic group is unsubstituted, i.e., it is unsubstituted.

[0053] The term "aryl" is recognized in the art and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracene, etc. The term "aryl" includes polycyclic systems having two or more carbon rings, wherein two or more carbon atoms are shared by two adjacent rings (the rings are "fused rings"), wherein at least one ring is an aromatic ring, and, for example, the other ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, and / or aryl. Unless otherwise stated, the aromatic ring may be substituted at one or more ring positions with, for example, halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, thioalkyl, imino, amide, carboxylic acid, -C(O)alkyl, -CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamide, sulfonamide, ketone, aldehyde, ester, heterocyclic, aryl or heteroaryl moiety, -CF3, -CN, etc. In some embodiments, the aromatic ring is substituted at one or more ring positions with halogens, alkyl, hydroxyl, or alkoxy. In some other embodiments, the aromatic ring is not substituted, i.e., it is unsubstituted. In some embodiments, the aryl group has a 6-10 membered ring structure.

[0054] The terms "heterocyclic group" and "heterocyclic group" are recognized in the art and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, or 3- to 7-membered rings, whose ring structure contains 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in a heterocyclic group can be specified using the Cx-Cx nomenclature, where x is an integer specifying the number of ring atoms. For example, a C3-C7 heterocyclic group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur. The name "C3-C7" indicates that the heterocycle contains a total of 3 to 7 ring atoms, including any heteroatoms occupying ring positions.

[0055] The terms “amine” and “amino” are well known in the art and refer to unsubstituted and substituted amines (e.g., monosubstituted or disubstituted amines), wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclic, alkenyl, and aryl groups.

[0056] The term "alkoxy" is recognized in the art and refers to an alkyl group as defined above having an oxygen group attached to it. Representative alkoxy groups include methoxy, ethoxy, tert-butoxy, etc.

[0057] An "ether" is two hydrocarbons covalently linked by oxygen. Therefore, the substituents of the alkyl group that make the alkyl group an ether are or similar to alkoxy substituents, for example, they can be represented by -O-alkyl, -O-alkenyl, -O-ynyl, etc.

[0058] As used in this article, the term "carbonyl" refers to the group -C(O)-.

[0059] The term "oxo" refers to the divalent oxygen atom -O-.

[0060] As used herein, the term "formamide" refers to the group -C(O)NRR', where R and R' may be the same or different. For example, R and R' may independently be alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclic.

[0061] As used herein, the term "carboxyl" refers to the group -COOH or its corresponding salt, such as -COONa, etc.

[0062] As used herein, the terms “amide” or “acylamino” or “amide group” refer to form -R 1 C(O)N(R 2 )-、-R 1 C(O)N(R 2 )R 3 -、-C(O)NR 2 R 3 or -C(O)NH2 groups, wherein, for example, R 1 R 2 and R3 Each of these groups is independently alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydrogen, hydroxyl, ketone, or nitro.

[0063] The compounds disclosed herein may contain one or more chiral centers and / or double bonds, and thus exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. When used herein, the term "stereoisomer" comprises all geometric isomers, enantiomers, or diastereomers. Depending on the configuration of the substituents surrounding the stereocarbon atom and / or the observed optical activity, these compounds may be represented by the symbols "R" or "S" or "+" or "-". This invention includes various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be named using nomenclature (±), but those skilled in the art will recognize that the structure may implicitly represent the chiral center. It should be understood that, unless otherwise stated, the chemical structure, such as a graphical description of a general chemical structure, covers all stereoisomers of the specified compound. This document also focuses on compounds comprising, substantially comprising, or composed of enantiomerically pure compounds, which may comprise at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of the specified compound, which is substantially composed of or composed of (e.g., at least about 99% of the R enantiomer of the specified compound).

[0064] Substituted heterocycles for inhibiting the bioactivity of C-MYC and their applications

[0065] This article discloses substituted heterocycles. The disclosed heterocycles have been shown to inhibit the biological activity of c-MYC. The disclosed substituted heterocycles may include substituted pyrazoles, substituted pyrimidines, and substituted triazoles.

[0066] In some embodiments, the disclosed substituted heterocycle may include a substituted pyrazole having Formula I: in R 1 It is hydrogen, or R 1It is an aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 1 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 The alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), R 2 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; R 3 It can be hydrogen, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), benzyl, hydroxyl, halogen, amide, hydrazone, carbonyl, carboxyl or alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, or R 4 It is aryl (e.g., phenyl) or benzyl; R 4Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy); R 5 It is an alkyl group (e.g., C1-C6 alkyl), alkoxy group (e.g., C1-C6 alkoxy), haloalkyl group (e.g., trifluoromethyl), haloalkoxy group (e.g., trifluoromethoxy), hydroxyl group or halogen; R 6 It is hydrogen, amino, alkyl, or R 6 It is aryl (e.g., phenyl) or benzyl; R 6 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy), or R 6 and R 5 Together they form a pattern The ring structure; R 7 It is hydrogen or halogen, or R 7 The alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; Choose any location, provided that R is the condition. 4 and R 6 At least one of them is hydrogen; Optionally, the condition is that if R 5 If it is hydrogen, then p is 1 and m is 1; and Optionally, the condition is that if R 1 (CH2) n (X) p- is hydrogen, hydroxyl or alkyl, and R 5 If it is a hydroxyl group, then m is 1, or R 2 and R 3 At least one of them is not hydrogen.

[0067] In some of the disclosed embodiments of substituted pyrazoles, R 2 and R 7 At least one of them is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 and R 7 Optionally, it is substituted at one or more positions with one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl. In some embodiments of the disclosed compound, m is 0 and R 2 It is hydrogen, or R 7 It is hydrogen.

[0068] In some of the disclosed embodiments of substituted pyrazoles, R 2 It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; and R 7 It is hydrogen.

[0069] In some embodiments of these disclosed substituted pyrazoles, m is 0 and R 2 It is hydrogen; and R 7It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0070] In the disclosed formula I, Pyr is a pyrazole ring with two non-adjacent double bonds, wherein the substituted pyrazole has formula I(i) or I(ii):

[0071] Specifically, the substituted pyrazole can have the formula Ia(i), Ia(ii), Ib(i), Ib(ii), Ic(i), or Ic(ii):

[0072] In some embodiments, the disclosed substituted heterocycle may include a substituted pyrazole having formula II: in Y is either C or N; R 1 It is hydrogen, or R 1 It is an aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 1 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2)n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 2 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. R 3 It can be hydrogen, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), benzyl, hydroxyl, halogen, amide, hydrazone, carbonyl, carboxyl or alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, or R 4 It is aryl (e.g., phenyl) or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy); R 6 It is hydrogen, amino, alkyl, or R 6 It is aryl (e.g., phenyl) or benzyl; R 6 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy); and R 7 It is hydrogen or halogen, or R 7The alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; Choose any location, provided that R is the condition. 4 and R 6 At least one of them is hydrogen; Optionally, the condition is that if R 5 If it is hydrogen, then p is 1 and m is 1; and Optionally, the condition is that if R 1 (CH2) n (X) p - is hydrogen, hydroxyl or alkyl, and R 5 If it is a hydroxyl group, then m is 1, or R 2 and R 3 At least one of them is not hydrogen.

[0073] In some of the disclosed embodiments of substituted pyrazoles, R 2 and R 7 At least one of them is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 and R 7 Optionally, it is substituted at one or more positions with one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl. In some embodiments of the disclosed compound, m is 0 and R 2 It is hydrogen, or R 7 It is hydrogen.

[0074] In some of the disclosed embodiments of substituted pyrazoles, R 2It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; and R 7 It is hydrogen.

[0075] In some embodiments of these disclosed substituted pyrazoles, m is 0 and R 2 It is hydrogen; and R 7 It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0076] In particular, substituted pyrazoles can have formula IIa:

[0077] In some embodiments, the disclosed substituted heterocycle may include a substituted pyrimidine having formula III: in: R 1 It is hydrogen, or R 1It is an aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 1 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. n is 0, 1, or 2; p is 0 or 1; X is O, NH, or R. 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 2 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. R 4 It is hydrogen, amino, alkyl, or R 4 It is aryl (e.g., phenyl) or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy); R 5It is an alkyl group (e.g., C1-C6 alkyl), an alkoxy group (e.g., C1-C6 alkoxy), a haloalkyl group (e.g., trifluoromethyl), a haloalkoxy group (e.g., trifluoromethoxy), a hydroxyl group, or a halogen; and R 7 It is hydrogen or halogen, or R 7 The alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0078] In some embodiments of these disclosed substituted pyrimidines, R 2 and R 7 At least one of them is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 and R 7 Optionally, it is substituted at one or more positions with one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl. In some embodiments of the disclosed compound, m is 0 and R 2 It is hydrogen, or R 7 It is hydrogen.

[0079] In some embodiments of these disclosed substituted pyrimidines, R 2It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; and R 7 It is hydrogen.

[0080] In some embodiments of these disclosed substituted pyrimidines, m is 0 and R 2 It is hydrogen; and R 7 It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0081] In particular, the substituted pyrimidines can have formula IIIa or IIIb:

[0082] In some embodiments, the disclosed substituted heterocycle may include a substituted pyrazole having formula IV: in: R 1 It is hydrogen, or R 1It is an aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 1 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. n is 0, 1, or 2; p is 0 or 1; X is O, NH, or R. 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; Y is either N or C; Z is either N or C; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 2 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. R 4 It is hydrogen, amino, alkyl, or R 4 It is aryl (e.g., phenyl) or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy (e.g., phenoxy), and alkylaryloxy (e.g., benzyloxy); R 5 It is an alkyl group (e.g., C1-C6 alkyl), an alkoxy group (e.g., C1-C6 alkoxy), a haloalkyl group (e.g., trifluoromethyl), a haloalkoxy group (e.g., trifluoromethoxy), a hydroxyl group, or a halogen; and R 7 It is hydrogen or halogen, or R 7 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 7 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0083] In some of the disclosed embodiments of substituted pyrazoles, R 2 and R 7 At least one of them is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 and R 7 Optionally, it is substituted at one or more positions with one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl. In some embodiments of the disclosed compound, m is 0 and R 2 It is hydrogen, or R 7 It is hydrogen.

[0084] In some of the disclosed embodiments of substituted pyrazoles, R 2It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; and R 7 It is hydrogen.

[0085] In some embodiments of these disclosed substituted pyrazoles, m is 0 and R 2 It is hydrogen; and R 7 It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 7 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0086] In some embodiments, the disclosed substituted heterocycle may include a substituted triazole having formula V: in: R 1 It is hydrogen, or R 1 It is an aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 1It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 2 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl. R 5 It is an alkyl group (e.g., C1-C6 alkyl), an alkoxy group (e.g., C1-C6 alkoxy), a haloalkyl group (e.g., trifluoromethyl), a haloalkoxy group (e.g., trifluoromethoxy), a hydroxyl group, or a halogen; and R 7 It is hydrogen or halogen, or R 7 It is an alkyl, aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), optionally R 7 It is substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0087] In some of the disclosed implementations of these substituted triazoles, R 2 and R 7 At least one of them is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 and R 7 Optionally, it is substituted at one or more positions with one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl. In some embodiments of the disclosed compound, m is 0 and R 2 It is hydrogen, or R 7 It is hydrogen.

[0088] In some of the disclosed implementations of these substituted triazoles, R 2 It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 2 Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; and R 7 It is hydrogen.

[0089] In some embodiments of these disclosed substituted triazoles, m is 0 and R 2 It is hydrogen; and R 7 It is aryl (e.g., phenyl), benzyl, heteroaryl (e.g., N-pyridinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, 1,3-benzodioxacyclopenten-5-yl, 1,3-benzodioxacyclopenten-6-yl, furan-2-yl, furan-3-yl), cycloalkyl (e.g., cyclohexyl), cycloheteryl (e.g., piperidinyl, morpholinyl), and R 7Optionally substituted at one or more positions by one or more of alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), haloalkyl (e.g., trifluoromethyl), haloalkoxy (e.g., trifluoromethoxy), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

[0090] The general formulas of the compounds disclosed herein should be interpreted as encompassing all possible stereoisomers, enantiomers, or epiisomers of the compounds, except where the general formula indicates a specific stereoisomer, enantiomer, or epiisomer. The general formulas of the compounds disclosed herein should be interpreted as including salts, esters, amides, or solvates of the compounds.

[0091] Uses of the disclosed compounds that inhibit C-MYC activity

[0092] The disclosed compounds may exhibit one or more biological activities. The disclosed compounds may inhibit the binding of the MYC / Max complex to DNA (e.g., in DNA gel migration assays). In some embodiments, the disclosed compounds inhibit the binding of the MYC / Max complex to DNA by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% at concentrations below about 100 μM, 50 μM, 10 μM, 1 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, or lower. The disclosed compounds may not cause significant DNA damage (e.g., in rH2AX staining assays at concentrations greater than 0.001 μM, 0.005 μM, 0.01 μM, 0.1 μM, 1.0 μM, 10 μM, 100 μM, or higher). The disclosed compounds can inhibit the growth of cells expressing c-MYC (preferably at concentrations below about 100 μM, 50 μM, 10 μM, 1 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, 0.001 μM or lower, by at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99%). The disclosed compounds can not inhibit the growth of cells not expressing c-MYC (preferably at concentrations greater than about 0.001 μM, 0.005 μM, 0.01 μM, 0.5 μM, 0.1 μM, 1.0 μM, 10 μM and 100 μM or higher, by no more than 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2% or lower). This article also focuses on concentration ranges, for example, concentration ranges defined by endpoint concentrations selected from 0.001 μM, 0.005 μM, 0.01 μM, 0.5 μM, 0.1 μM, 1.0 μM, 10 μM and 100 μM.

[0093] The disclosed compounds can effectively inhibit the cell proliferation of cancer cells, including cancer cells that express c-MYC and whose proliferation is inhibited by suppressing the biological activity of c-MYC. The disclosed compounds can effectively inhibit the cell proliferation of one or more types of cancer cells, including: multiple myeloma cells, such as MM.1S cells; leukemia cells, such as CCRF-CEM, HL-60(TB), MOLT-4, RPMI-8226, and SR; non-small cell lung cancer cells, such as A549 / ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, and NCI-H522; colon cancer cells, such as COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-620; CNS; SF-268, SF-295, SF-539, SNB-19, SNB-75, and U251; and melanoma cancer cells, such as LOX. IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, and UACC-62; ovarian cancer cells such as IGR-OV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI / ADR-RES, and SK-OV-3; renal cancer cells such as 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, and UO-31; prostate cancer cells such as DU-145 and PC-3; and breast cancer cells such as MCF7, MDA-MB-231 / ATCC, MDA-MB-468, HS 578T, BT-549, and T-47D.

[0094] The cell viability methods disclosed in this art, including colorimetric assays using dyes such as MTT, XTT, and MTS to assess cell viability, can be used to evaluate the cell proliferation and inhibitory effects of the disclosed compounds. Preferably, in the selected assay, the disclosed compounds have an IC50 concentration of 10 μM, 5 μM, 1 μM, 0.5 μM, 0.01 μM, 0.005 μM, 0.001 μM, or less. 50 .

[0095] The disclosed compounds can be formulated into anticancer therapeutic agents, including those for hematologic malignancies, breast, lung, pancreatic, and prostate cancer. They can also be formulated into anti-inflammatory therapeutic agents.

[0096] The compounds used in the methods disclosed herein can be formulated into pharmaceutical compositions comprising: (a) a therapeutically effective amount of one or more of the compounds disclosed herein; and (b) one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition may contain from about 0.1 to 2000 mg (preferably from about 0.5 to 500 mg, more preferably from about 1 to 100 mg) of the compound. The pharmaceutical composition can be administered to provide a daily dose of from about 0.1 to about 1000 mg / kg body weight (preferably from about 0.5 to about 500 mg / kg body weight, more preferably from about 50 to about 100 mg / kg body weight). In some embodiments, after the pharmaceutical composition is administered to a subject (e.g., about 1, 2, 3, 4, 5, or 6 hours after administration), the concentration of the compound at the site of action can be within a range defined by an endpoint selected from 0.001 μM, 0.005 μM, 0.01 μM, 0.5 μM, 0.1 μM, 1.0 μM, 10 μM, and 100 μM (e.g., 0.1 μM to 1.0 μM).

[0097] The disclosed compounds and pharmaceutical compositions comprising the disclosed compounds may be administered in treatments for subjects in need of such treatment. For example, subjects in need of such treatment may include subjects with a proliferative disorder, disorder, or condition such as cancer (e.g., multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer).

[0098] In some embodiments of the disclosed treatment methods, the subject may be administered the compound in doses as low as the following: 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 5 5 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg or 2000 mg, once daily, twice daily, three times daily, four times daily, once weekly, twice weekly or three times weekly, for the treatment of a subject’s disease or disorder. In some implementations, subjects are administered compounds in doses up to the following amounts: 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 5 7.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg, once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times weekly, for the treatment of a subject's disease or disorder. The minimum and / or maximum dose of the compound may include doses falling within a dose range having any of these disclosed doses as endpoints (e.g., 2.5 mg–200 mg).

[0099] In some implementations, the minimum dose level used to achieve the therapy in the disclosed treatment method may be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng / kg body weight in a subject. In some implementations, the highest dose level used to achieve the therapy in the disclosed treatment method may be no more than about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng / kg body weight in the subject. The minimum and / or maximum dose levels used to achieve the therapy in the disclosed treatment methods may include dose levels falling within a dose range having any of these disclosed dose levels as endpoints (e.g., 500-2000 ng / kg body weight subjects).

[0100] Although any pharmaceutically acceptable dosage form may be used, pharmaceutical compositions in which the compounds used in the methods disclosed herein may be formulated into solid dosage forms. Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form may be, for example, a melt-down formulation, a controlled-release formulation, a lyophilized formulation, a delayed-release formulation, a prolonged-release formulation, a pulsatile-release formulation, a mixture of immediate-release and controlled-release formulations, or a combination thereof.

[0101] The compounds used in the methods disclosed herein can be formulated into pharmaceutical compositions including a carrier. For example, the carrier may be selected from proteins, carbohydrates, sugars, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste.

[0102] The compounds used in the methods disclosed herein may include one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, humectants, disintegrants, and effervescent agents. Fillers may include lactose monohydrate, anhydrous lactose, and various starches; examples of binders are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, for example... PH101 and PH102, microcrystalline cellulose and silicified microcrystalline cellulose (ProSolv SMCC) TM Suitable lubricants, including agents that affect the flowability of the powder to be compressed, may include colloidal silica, for example... 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners may include any natural or artificial sweeteners, such as sucrose, xylitol, sodium saccharin, cyclosulfonates, aspartame, and acetylpanthen. Examples of flavoring agents are... (Trademarks (MAFCO's trademarks), bubble gum flavorings and fruit flavorings, etc. Examples of preservatives may include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of benzoic acid (e.g., butylparaben), alcohols (e.g., ethanol or benzyl alcohol), phenolic compounds (e.g., phenol), or quaternary ammonium compounds (e.g., benzalkonium chloride).

[0103] Suitable diluents may include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dicalcium phosphate, sugars, and mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, for example... PH101 and PH1022; lactose, such as lactose monohydrate, anhydrous lactose, and DCL21; calcium hydrogen phosphate, such as Mannitol; starch; sorbitol; sucrose; and glucose.

[0104] Suitable disintegrants include mildly cross-linked polyvinylpyrrolidone, corn starch, potato starch, corn starch and modified starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl ketone, sodium glycolate starch and mixtures thereof.

[0105] Examples of effervescent agents are effervescent pairs, such as organic acids and carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, as well as acid anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent pair may be present.

[0106] The compounds used in the methods disclosed herein can be formulated into pharmaceutical compositions for delivery via any suitable route. For example, the pharmaceutical compositions can be administered orally, intravenously, intramuscularly, subcutaneously, topically, and pulmonaryly. Examples of pharmaceutical compositions for oral administration include capsules, syrups, concentrates, powders, and granules. In some embodiments, the compounds are formulated into compositions for oral administration (e.g., in a solvent such as 5% DMSO, or in an oil such as a vegetable oil).

[0107] The compounds used in the methods disclosed herein can be administered in conventional dosage forms prepared according to conventional methods known in the art by mixing the active ingredient with a standard pharmaceutical carrier or diluent. These methods may involve appropriately mixing, granulating, pressing, or dissolving the ingredients into the desired formulation.

[0108] Pharmaceutical compositions comprising the said compound may be adapted for administration via any suitable route, such as oral (including sublingual or oral), rectal, nasal, topical (including sublingual, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations may be prepared by any method known in the pharmaceutical field, such as by mixing the active ingredient with a carrier or excipient.

[0109] Pharmaceutical compositions suitable for oral administration may exist in discrete units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whisks; or oil-in-water or water-in-oil liquid emulsions.

[0110] Pharmaceutical compositions suitable for transdermal administration can exist as discrete patches intended to maintain close contact with the recipient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch via iontophoresis.

[0111] Pharmaceutical compositions suitable for topical application can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, immersion dressings, sprays, aerosols, or oils, and may contain appropriate conventional additives such as preservatives, solvents to aid drug penetration, and emollients in ointments and creams.

[0112] For application to the eye or other external tissues, such as the mouth and skin, the pharmaceutical composition is preferably applied in the form of a topical ointment or cream. When formulated as an ointment, the compound may be used with a paraffin or a water-miscible ointment base. Alternatively, the compound may be formulated as a cream with an oil-in-water or water-in-oil emulsion base. Pharmaceutical compositions suitable for topical application to the eye include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.

[0113] When the carrier is solid, suitable pharmaceutical compositions for nasal administration include coarse powder having a particle size (e.g., in the range of 20-500 micrometers) which is applied in a manner that takes nasal smoke (i.e., by rapid inhalation through the nasal passage from a powder container near the nose). If the carrier is liquid, suitable formulations for administration as nasal sprays or drops include aqueous or oil solutions of the active ingredient.

[0114] Pharmaceutical compositions suitable for parenteral administration include: aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes, making the formulation isotonic with the intended recipient's blood; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. The formulations may be present in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0115] Orally administered tablets and capsules may be in unit-dose presentation and may contain conventional excipients, such as binders like syrup, gum arabic, gelatin, sorbitol, tragali gum, or polyvinylpyrrolidone; fillers like lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine; tableting lubricants like magnesium stearate, talc, polyethylene glycol, or silica; disintegrants like potato starch; or acceptable wetting agents like sodium lauryl sulfate. Tablets may be coated according to methods well-known in conventional pharmaceutical practice. Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may exist as a dry product to be reconstituted with water or other suitable carriers prior to use. Such liquid formulations may contain conventional additives, such as suspending agents, such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, such as lecithin, dehydrated sorbitan monooleate or gum arabic; non-aqueous media (which may include edible oils), such as almond oil, oil esters, such as glycerin, propylene glycol or ethanol; preservatives, such as methylparaben or propylparaben or sorbic acid, and, if desired, conventional flavoring agents or coloring agents.

[0116] Combination therapies and pharmaceutical compositions

[0117] The disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered in treatment methods. For example, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered in methods for treating proliferative disorders and disorders. Proliferative disorders and disorders treated by the disclosed methods may include, but are not limited to, cancers selected from: multiple myeloma, leukemia, non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma, ovarian cancer, kidney cancer, prostate cancer, and breast cancer.

[0118] Optionally, the disclosed compound or a pharmaceutical composition comprising the disclosed compound may be administered together with additional therapeutic agents (optionally in combination) to treat proliferative diseases and conditions. In some embodiments of the disclosed method, one or more additional therapeutic agents are administered together with the disclosed compound or a pharmaceutical composition comprising the disclosed compound, wherein the additional therapeutic agents are administered before, simultaneously with, or after the administration of the disclosed compound or the pharmaceutical composition comprising the disclosed compound. In some embodiments, the disclosed pharmaceutical composition is formulated to comprise the disclosed compound and further comprises one or more other therapeutic agents, such as one or more other therapeutic agents for treating proliferative diseases and disorders.

[0119] In some implementations, other therapeutic agents may include, but are not limited to, therapeutic agents for treating leukemia and lymphoma, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and non-Hodgkin's lymphoma.

[0120] In some embodiments, other therapeutic agents may include, but are not limited to, antimetabolite antitumor agents that inhibit DNA synthesis. Suitable antimetabolite antitumor agents that inhibit DNA synthesis may include, but are not limited to, nucleoside and / or nucleotide derivatives. Suitable nucleoside and / or nucleotide derivatives may include, but are not limited to, cytosine arabinoside (ara-C), otherwise referred to as cytarabine. Example

[0121] The following examples are exemplary and are not intended to limit the scope of the claimed subject matter.

[0122] Example 1: Identification of Small Molecule Inhibitors of C-MYC DNA Binding Activity

[0123] introduction

[0124] MYC is the most frequently amplified oncogene in human cancers. It has been widely validated in many tumor histologies as essential for tumor initiation and maintenance. Numerous studies have provided conclusive evidence that pharmacological targeting of MYC directly influences tumor progression. One example is OmoMYC, a dominant-negative peptide of MYC that competitively binds to MYC in a manner that prevents MYC-Max heterodimerization. OmoMYC expression, both in vitro and in vivo, suggests rapid growth arrest and downregulation of MYC target genes in cancer cells. Small molecule inhibitors of MYC would be the optimal form for drug development. However, disrupting the MYC-Max interaction with small molecules is difficult because there is no obvious binding region at the interface. To date, more than 30 small molecules have been documented to possess MYC inhibitory activity in vitro, but evidence of their in vivo activity is lacking, possibly due to their poor pharmacokinetic properties. Among these compounds, 10058-f4 and 10075-G5 are well-known for their specificity and have relatively well-defined mechanisms for disrupting MYC-Max binding. However, in vivo studies have been disappointing due to their rapid metabolism. Therefore, developing novel MYC inhibitors with high potency, specificity, and good drug-like properties is crucial for effective MYC targeting.

[0125] To this end, we performed computer screening to identify compounds that might inhibit c-MYC binding to DNA. These compounds were tested on several cell-based assays to determine the most active targets. Min-9 (NUCC-176234) and its related analogs were confirmed to prevent c-MYC / DNA binding, exhibiting the highest hit rate. We then synthesized a series of novel structural analogs and tested them on the same c-MYC-related assays. Our new compounds demonstrated superior efficacy in inhibiting c-MYC / DNA binding. The compounds developed using our novel approach exhibit significantly improved pharmacodynamic properties compared to existing small molecules (e.g., 10058-f4), thus representing an excellent starting point for developing therapeutics targeting MYC.

[0126] result

[0127] In the absence of a regular small molecule ligand binding bag in the c-MYC / Max / DNA ternary complex, we applied several independent computational methods to increase our chances of successfully identifying novel small molecule inhibitors. (See [link to documentation]) Figure 1We performed a computer-based screening of ten million drug-like libraries. After removing confounding and non-drug-like compounds using the PAINS filter, we applied two different methods to screen the ZINC compound database. The first method was based on a three-layer docking protocol using published MYC / Max crystal structures that bind to DNA. After defining the hypothetical ligand binding sites reported in the literature, the compound library was screened using a docking tool. The second method was based on establishing a pharmacophore model, taking into account 32 compounds reported to inhibit MYC, and screening the ZINC database against this pharmacophore. We obtained 69 hits from the structure-based screening and 60 hits from the ligand-based pharmacophore screening, for a total of 32 compounds between the two methods.

[0128] To test the compounds, we evaluated computer-simulated hit records in the MYC E-Box luciferase reporter molecular assay to determine the effects of these compounds (designated Min-1 to Min-32) on MYC transcriptional activity. Figure 2 As shown, approximately 10 compounds exhibited similar or better activity compared to the 25 μM positive control 10058-F4. (See...) Figure 2 ).

[0129] We next examined the ability of the compounds to selectively inhibit the proliferation of wild-type cells expressing MYC relative to cells with MYC knockout. We tested the first 13 active compounds in the first screening assay. Figure 3 A schematic diagram showing the growth inhibition of each compound on wild-type and MYC knockout rat fibroblasts with maximal selectivity is presented. More than half of the tested compounds showed better growth inhibition against MYC WT cells compared to MYC KO cells. Min9-S7 (NUCC-0176248) is very promising due to its low effective concentration (6 μM) and high specificity. Min9-S9 (NUCC-0176250) also showed significant selectivity at an acceptable dose (50 μM).

[0130] Min9 (NUCC-0176234) was also tested in cell viability analysis of cMYC wild-type (WT) and cMYC KO lines. Figure 4 As shown, the cell viability of this compound in WT cells was much lower than that in KO cells, which suggests a mechanism directly related to cMYC.

[0131] We also tested the effects of the best-hit compound Min9 (NUCC-0176234) and newly synthesized analogs on the binding of MYC / Max to DNA using electrophoretic mobility shift assay (EMSA). (See...) Figure 5 and Figure 6 We anticipated that the active compound would impair the binding of MYC / Max to DNA. The inhibitory effects of several structural analogs of Min9 on MYC-DNA binding were tested at multiple doses, and we observed dose-dependent inhibition. (See [link to relevant documentation]) Figure 7 ).

[0132] The ability of Min9 (NUCC-0176234) to induce DNA damage was also tested in an rH2AX staining assay. We did not expect cMYC targets to produce significant DNA damage. However, the effects of compounds that act directly on DNA (e.g., doxorubicin) were indeed present. We observed virtually no DNA damage induced by Min9 (NUCC-0176234). (See...) Figure 6 ).

[0133] The in vitro metabolism of NUCC-176242 and NUCC-176248 was tested using mouse liver microsomes and mouse S9 fractions. (See also...) Figure 9 Based on the comparison between the mouse S9 fraction and NUCC-176248, NUCC-176242 exhibits significant metabolic activity, which may be due to the conjugation of S9 on the N-1 nitrogen atom of the pyrazole ring.

[0134] The pharmacokinetics of NUCC-176242 and NUCC-176248 were investigated in mice by intravenous administration of a dose of 5 mg / kg and measurement of changes in plasma concentration over time. (See also...) Figure 10 The observed in vivo metabolism of NUCC-176242 and NUCC-176248 was highly correlated with the in vitro metabolism of NUCC-176242 and NUCC-176248 tested above.

[0135] Chemical

[0136] General experimental procedures. Unless otherwise specified, all chemical reagents were purchased from commercial suppliers and can be used without further purification. Anhydrous solvents were purchased from Sigma-Aldrich and used as needed. Molecular sieve drying. DCM and THF were purified via an activated alumina bed. Normal-phase rapid column chromatography was performed using a Biotage KP-Sil 50 μm silica column and ACS-grade solvents in an EM Reagent 0.25 mm silica 60F system. 254Analytical thin-layer chromatography (TLC) was performed on the plate, and colorimetric analysis was performed using UV light or iodine vapor. Liquid chromatography / mass spectrometry (LCMS) analysis was performed using a Waters Acquity-H UPLC system with a 2.1 mm × 50 mm, 1.7 μm reversed-phase BEH C18 column and LCMS-grade solvent. A gradient elution was performed over 2 minutes from 95% water + 0.1% formic acid / 5% acetonitrile + 0.1% formic acid to 95% acetonitrile + 0.1% formic acid / 5% water + 0.1% formic acid, followed by eluent flow at 0.85 mL / min for 1 minute. Total ion traces for both positive and negative electrospray ionization (ESI+ / ESI-) were obtained. Protons ( 1 H) and carbon ( 13 C) NMR spectra were recorded using a Bruker Avance III spectrometer with a direct cryogenic probe. Chemical shifts are reported in ppm (δ), and residual non-deuterated solvents were used as internal standards for reference. 1 HNMR and 13 C NMR chemical shifts are reported to two decimal places. The proton coupling constant is expressed in Hertz (Hz). The following abbreviations are used to denote the spin multiplicity of proton NMR: s = singlet, d = doublet, t = triplet, q = quartet, m = multiply, brs = broad singlet, dd = doublet, dt = doublet triplet, quin = quintet, tt = triplet triplet. In some cases, 13 Overlapping signals will appear in the C NMR spectrum.

[0137] Representative examples of general synthetic methods

[0138] A. Synthesis Method A Synthesis Method A

[0139] Step 1. Add bromoacetonitrile (1 equivalent) to a solution of phenol (1 equivalent) in 100 mL of acetone, followed by potassium carbonate (1.5 equivalent). Stir the solution at 60 °C for 4.5 h. Stop the reaction by adding 30 mL of NaHCO3 aqueous solution and water, and extract with EtOAc (3 x 30 mL). Rinse the combined organic layers with salt water once, and dry with anhydrous Na2SO4. Remove the solvent under reduced pressure, and purify the residue by silica gel chromatography.

[0140] Step 2. Add a solution of dioxane in HCl (10 equivalents) to a 1M solution of acetonitrile-phenoxy intermediate (1 equivalent) in 6.5 mL of benzene in an ice bath. Stir the resulting solution for 1 h, then slowly add resorcinol (1 equivalent) and ZnCl2 (1 equivalent) in 10 mL of diethyl ether. Stir the resulting solution from 0 °C to RT for 16 h. Centrifuge the resulting suspension to separate the solid. Wash the solid with water and dry under vacuum.

[0141] Step 3. Heat the suspension of O-phenoxyacetophenone (1 mmol) with TFFA (5 equivalents) and pyridine (5 equivalents) at 120 °C for 4 h. Then cool to rt. In some cases, precipitate the product; in others, add water and extract with EtOAc (3 x 10 mL). Wash the combined organic layers with brine, dry with Na2SO4, filter, and concentrate. Purify the residue by silica gel chromatography.

[0142] Step 4. Heat a suspension of phenoxy-chromone (1 equivalent), K2CO3 (2 equivalents), and haloalkane (1.1 equivalents) in 5 mL of acetone (0.8 M) at 60 °C for 16 h. Filter the reaction system through a funnel and remove the solvent under reduced pressure. Grind the crude product together with water and dry under reduced pressure to dryness.

[0143] Step 5. The solution of the above phenoxy-chromone (1 equivalent) and the desired hydrazine (3 equivalents) in 2 mL of EtOH (0.1 M) is heated at 70 °C for 45 minutes. The solution is cooled to room temperature and concentrated. The solid is purified directly by silica gel chromatography (n-hexane / ethyl acetate = 5:1-1:1) to obtain the desired pyrazole.

[0144] Example

[0145] NUCC-200683: 1 H NMR (500MHz, CDCl3) δ7.81 (dd, J=7.9, 1.6Hz, 1H), 7.18 (td, J=7.7, 1.6Hz, 1H), 7.10-7.02 (m , 2H), 6.92-6.86 (m, 2H), 6.86-6.79 (m, 2H), 2.56 (q, J=7.6Hz, 2H), 1.17 (t, J=7.6Hz, 3H)ppm.

[0146] NUCC-198411: 1H NMR(500MHz,CDCl3)δ7.00-6.92(m,3H),6.80-6.68(m,2H),6.44-6.38(m,1H),6.32(d,J=8.4Hz,1H),2.52(q,J=7.8Hz,2H),1.13(t,J=7.4Hz,3H)ppm。

[0147] NUCC-198406: 1 H NMR(500MHz,CDCl3)δ7.64(d,J=8.6Hz,1H),7.06(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),6.41(d,J=2.4Hz,1H),6.33(dd,J=8.6,2.4Hz,1H),2.56(q,J=7.5Hz,2H),1.17(t,J=7.7Hz,3H)ppm。

[0148] NUCC-196355: 1 H NMR(500MHz,CDCl3)δ7.69(d,J=8.7Hz,1H),7.47(d,J=2.0Hz,1H),7.42(d,J=8.3Hz,1H),7.19(dd,J=8.3,2.0Hz,1H),7.07(d,J=8.7Hz,2H),6.86-6.76(m,2H),6.48(d,J=13.3Hz,2H),4.95(s,2H),2.57(q,J=7.6Hz,2H),1.18(t,J=7.6Hz,3H)ppm。

[0149] NUCC-196342: 1 H NMR(500MHz,CDCl3)δ7.69(d,J=8.8Hz,1H),7.43(dd,J=7.7,1.5Hz,1H),7.35-7.27(m,4H),7.06(ddd,J=8.3,7.7,1.6Hz,1H),6.96(td,J=7.6,1.4Hz,1H),6.65(dd,J=8.3,1.5Hz,1H),6.50(d,J=14.5Hz,2H),4.97(s,2H)ppm。

[0150] NUCC-196295: 1H NMR (400MHz, CDCl3) δ7.70 (d, J=8.7Hz, 1H), 7.37 (s, 1H), 7.28 (dd, J=5.4, 1.2Hz, 2H), 7.07 (d, J=8.7H z, 2H), 6.86-6.79 (m, 2H), 6.50 (s, 2H), 4.98 (s, 2H), 2.57 (q, J=7.6Hz, 1H), 1.18 (t, J=7.6Hz, 2H)ppm.

[0151] B. Synthesis Method B Synthesis Method B

[0152] Step 1. Add sodium 2,2,2-trifluoroacetate (9.84 g, 72.36 mmol, 2.2 equivalents) to a suspension of 1-(2,4-dihydroxyphenyl)ethyl-1-one (5.00 g, 32.89 mmol, 1 equivalent) in trifluoroacetic anhydride (18.50 mL, 131.56 mmol, 4 equivalents) in an autoclave. Cap the system and stir at 110 °C for 24 h. Cool the reaction system to approximately 70 °C and dilute with 200 mL of EtOAc. Neutralize the mixture by adding saturated K₂CO₃ aqueous solution until no more foaming is observed. Separate the layers and extract the aqueous phase with EtOAc (3 x 150 mL). Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Then concentrate the solution to 100–150 mL of EtOAc. Then, the flask was sealed at room temperature for 1-2 days to obtain a solid. The solid was filtered and dried under vacuum to obtain 4.09 g of pure 1, which was a white solid with a yield of 54%.

[0153] Then, pyridine (5.59 mL, 69.24 mmol, 4 equivalents) was added to a solution of the obtained solid (4 g, 17.31 mmol, 1 equivalent) and iodine (17.57 g, 69.24 mmol, 4 equivalents) in 110 mL of CHCl3. The resulting solution was stirred at room temperature for 16 h. Then, 120 mL of saturated Na2S2O3 aqueous solution was added, and the resulting mixture was stirred for 1 h. The organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure, and the residue was ground several times with diethyl ether to give a yellowish-white solid in 90% yield (5.55 g, 15.60 mmol): mp 205–206 °C. 1 H NMR (500MHz, CDCl3) δ8.11 (dd, J=8.9, 1.0Hz, 1H), 7.15 (dd, J=8.9, 1.0Hz, 1H), 6.77-6.69 (m, 1H), 6.36 (s, 1H)ppm.13 C NMR (126MHz, CDCl3) δ175.8, 161.5, 156.0, 152.5 (q, 2 J=39.1Hz), 128.1, 119.0, 118.6 (q, 1 J = 272.2 Hz), 117.5, 114.7, 110.9 ppm. LRMS (EI): Calculated mass value C 10 H5F3IO3+[M+H] + =356.9, measured value =357.1.

[0154] Step 2. A suspension of 7-hydroxy-3-iodo-2-(trifluoromethyl)-4H-chromen-4-one (1 g, 2.8 mmol, 1 equivalent), a haloalkane (3.4 mmol, 1.2 equivalent), and K₂CO₃ (0.77 g, 5.6 mmol, 2 equivalent) in 5 mL of acetone was heated at 60 °C for 16 h. The reaction mixture was filtered through a funnel, and the solvent was removed under reduced pressure. The crude product was ground together with water and dried under reduced pressure until dry.

[0155] Step 3. Effervesce the suspension of the above-mentioned alkylated chromone (0.34 mmol, 1 equivalent) with the corresponding boric acid (0.37 mmol, 1.1 equivalent), Na₂CO₃ (0.68 mmol, 2 equivalent), and Pd(dppf)Cl₂ (0.026 mmol, 0.08 equivalent) in a 3.5 mL mixture of 1:2:6 EtOH:water:toluene for 10 minutes under nitrogen. Then cover the flask and heat the mixture at 90 °C for 2 h. Cool the dark solution to room temperature and dilute with EtOAc. Separate the organic layer and extract the aqueous phase with EtOAc (3 x 3 mL). Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Remove the solvent under reduced pressure and purify the residue by silica gel chromatography.

[0156] Step 4. The solution of the above-mentioned chromone (0.2 mmol, 1 equivalent) and the desired hydrazine (0.6 mmol, 3 equivalent) in 2 mL of EtOH was heated at 70 °C for 45 minutes. The solution was cooled to room temperature and concentrated. The solid product (n-hexane / ethyl acetate = 5:1-1:1) was directly purified by silica gel chromatography to obtain the desired pyrazole.

[0157] Example

[0158] NUCC-201634: 1H NMR(500MHz,CDCl3)δ7.75(d,J=2.2Hz,1H),7.58(dd,J=15.0,8.5Hz,2H),7.52(dd,J=8.5,2.2Hz,1H),6.87(s,1H),6.65(d,J=8.8Hz,1H),3.97(t,J=6.5Hz,2H),1.63-1.47(m,5H),0.84(d,J=6.5Hz,6H)ppm。

[0159] NUCC-201632: 1 H NMR(500MHz,MeOH-d4)δ8.82(d,J=2.1Hz,1H),8.77(d,J=2.1Hz,1H),8.13(t,J=2.1Hz,1H),7.33-7.25(m,2H),7.23(d,J=8.6Hz,1H),7.20-7.14(m,2H),6.77(d,J=8.6Hz,1H),6.56(s,1H),5.08(s,2H),3.80(s,3H)ppm。

[0160] NUCC-201227: 1 H NMR(500MHz,CDCl3)δ10.59(s,1H),7.80(d,J=2.1Hz,1H),7.57(dd,J=8.2,2.1Hz,1H),7.51(d,J=8.2Hz,1H),7.47(d,J=8.7Hz,1H),6.90(s,1H),6.58(d,J=8.7Hz,1H),3.97(s,3H),3.94(t,J=6.3Hz,2H),1.61(dq,J=7.9,6.4Hz,2H),1.33(h,J=7.5Hz,2H),0.87(t,J=7.4Hz,3H)ppm。

[0161] NUCC-201226: 1 H NMR(500 MHz,CDCl3)δ7.75(d,J=2.1 Hz,1H),7.59(d,J=8.3Hz,1H),7.50(dd,J=8.3,2.1 Hz,1H),7.18(d,J=8.5 Hz,1H),6.66(d,J=8.5 Hz,1H),6.54(s,1H),3.96(t,J=6.3 Hz,2H),3.82(s,3H),1.68-1.58(m,2H),1.36-1.29(m,2H),0.87(t,J=7.4 Hz,3H)ppm。

[0162] NUCC-0201213: 1 H NMR(500 MHz,CDCl3)δ8.81(dd,J=20.5,2.0 Hz,2H),8.03(d,J=1.9 Hz,1H),7.29-7.15(m,3H),6.70(d,J=8.6 Hz,1H),6.59(s,1H),5.50(s,1H),4.13-3.71(m,5H),1.78-1.31(m,5H),0.87(d,J=6.3 Hz,7H)ppm。

[0163] NUCC-201208: 1 H NMR(500 MHz,CDCl3)δ8.83(d,J=2.1 Hz,1H),8.79(d,J=2.1Hz,1H),8.04(t,J=2.1 Hz,1H),7.21(d,J=8.7 Hz,1H),6.70(d,J=8.7 Hz,1H),6.59(s,1H),4.01(t,J=6.4 Hz,2H),3.83(s,3H),1.71-1.43(m,3H),0.87(d,J=6.4 Hz,6H)ppm。

[0164] NUCC-0201207: 1 H NMR(500 MHz,CDCl3)δ8.93-8.66(m,2H),8.04(d,J=2.1 Hz,1H),7.34-7.12(m,2H),6.82-6.45(m,3H),5.85(s,1H),4.10-3.71(m,7H),1.65(q,J=6.8Hz,3H),1.40-1.01(m,9H),1.01-0.58(m,4H)ppm。

[0165] NUCC-201206: 1 H NMR(500 MHz,CDCl3)δ8.82(s,2H),8.01(d,J=2.3 Hz,1H),7.21(d,J=8.6 Hz,1H),6.70(d,J=8.6 Hz,1H),6.58(s,1H),4.00(t,J=6.3 Hz,2H),3.84(s,3H),1.65-1.53(m,3H),0.84(dd,J=6.5,2.6 Hz,6H)ppm。

[0166] NUCC-0201205: 1H NMR(500 MHz,CDCl3)δ8.74(d,J=43.1 Hz,2H),8.04(s,1H),7.30-7.14(m,2H),6.74-6.48(m,2H),3.96(t,J=6.1 Hz,3H),3.83(d,J=3.6 Hz,2H),1.62(q,J=6.7 Hz,3H),1.38-1.06(m,8H),0.82(t,J=6.8 Hz,4H)ppm。

[0167] NUCC-0201204: 1 H NMR(500 MHz,CDCl3)δ8.84-8.61(m,2H),8.04(s,1H),7.31-7.14(m,1H),6.67(d,J=8.6 Hz,1H),6.56(s,1H),3.97(t,J=6.2 Hz,2H),3.83(s,2H),1.69-1.54(m,2H),1.30(q,J=7.5Hz,2H),0.85(t,J=7.5Hz,3H)ppm。

[0168] NUCC-0201201:1H NMR(500MHz,CDCl3)δ8.05-7.74(m,5H),7.57(d,J=8.8Hz,1H),7.09-6.85(m,4H),6.75(d,J=8.7Hz,1H),6.59(d,J=8.1Hz,3H),4.95(s,2H),2.90(d,J=37.0Hz,2H)ppm。

[0169] NUCC-0201198: 1 H NMR(500MHz,CDCl3)δ10.79(s,1H),7.89(d,J=40.7Hz,3H),7.57(d,J=8.7Hz,1H),6.92(s,1H),6.64(d,J=8.8Hz,1H),3.95(t,J=6.2Hz,2H),1.77-1.49(m,2H),1.46-1.06(m,7H),0.81(t,J=6.8Hz,3H)ppm。

[0170] NUCC-0201197: 1 H NMR(500MHz,CDCl3)δ8.08-7.75(m,1H),3.92(t,J=6.3Hz,1H),1.65(q,J=6.8Hz,1H),0.87(t,J=7.4Hz,1H)ppm。

[0171] NUCC-0201196: 1 1H NMR (500 MHz, chloroform-d) δ 10.76 (s, 1H), 7.88 (d, J = 35.4 Hz, 3H), 7.57 (d, J = 8.7 Hz, 1H), 6.91 (s, 1H), 6.65 (d, J = 8.7 Hz, 1H), 3.98 (t, J = 6.3 Hz, 2H), 1.54 (dq, J = 37.9, 6.7 Hz, 3H), 0.83 (d, J = 6.5 Hz, 7H) ppm.

[0172] NUCC-0201195: 1 1H NMR (500 MHz, CDCl3) δ 11.63 (s, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 8.12 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.95 (s, 1H), 6.63 (d, J = 8.7 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 1.59 (ddt, J = 32.4, 13.3, 6.6 Hz, 6H), 0.87 (d, J = 6.4 Hz, 7H) ppm.

[0173] NUCC-0201193: 1 1H NMR (500 MHz, CDCl3) δ 11.25 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 6.96 (s, 1H), 6.63 (d, J = 8.7 Hz, 1H), 3.98 (t, J = 6.4 Hz, 2H), 1.81 - 1.45 (m, 7H), 1.32 (p, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 4H) ppm.

[0174] NUCC-0201192: 1 1H NMR (500 MHz, CDCl3) δ 11.64 (s, 2H), 8.87 (d, J = 77.5 Hz, 2H), 8.10 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.94 (s, 1H), 6.63 (d, J = 8.7 Hz, 1H), 3.96 (t, J = 6.3 Hz, 1H), 1.82 - 1.40 (m, 10H), 1.40 - 1.07 (m, 7H), 0.83 (t, J = 6.7 Hz, 3H) ppm.

[0175] NUCC-0201039: 11H NMR (500 MHz, MeOH-d4) δ 8.50 (s, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.38 - 7.24 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.04 - 6.91 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.22 - 4.99 (m, 2H), 4.41 (dd, J = 11.3, 6.9 Hz, 2H), 2.05 (s, 2H), 1.26 (t, J = 7.0 Hz, 3H) ppm; 13 13C NMR (126 MHz, MeOD) δ 157.2, 135.8, 133.1, 128.6, 128.1, 127.9, 125.3, 101.3, 101.3, 69.1, 62.4, 13.3 ppm.

[0176] NUCC-0201037: 1 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 48.4 Hz, 2H), 8.01 (s, 1H), 7.56 - 7.38 (m, 1H), 7.17 (td, J = 5.1, 2.3 Hz, 2H), 7.04 (dd, J = 8.1, 3.8 Hz, 2H), 6.80 (s, 1H), 6.67 - 6.55 (m, 1H), 4.94 (d, J = 4.0 Hz, 2H) ppm.

[0177] NUCC-0201036: 1 1H NMR (500 MHz, MeOH-d4) δ 6.49 (d, J = 1.8 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 6.29 - 6.09 (m, 3H), 5.83 - 5.65 (m, 4H), 5.47 (s, 1H), 5.32 (d, J = 8.7 Hz, 1H), 3.52 (s, 2H), 3.35 (s, 7H), 1.81 (s, 1H), 1.54 (s, 3H); 13 13C NMR (126 MHz, methanol-d4) δ 161.71, 155.20, 134.93, 134.06, 131.66, 128.50, 126.96, 126.72, 126.63, 99.87, 67.78, 41.46 ppm.

[0178] NUCC-02X031: 1H NMR(500MHz,CDCl3)δ7.89(d,J=5.8Hz,2H),7.76(d,J=5.6Hz,1H),7.64-7.36(m,1H),6.82(d,J=5.9Hz,1H),6.56(dd,J=10.6,4.7Hz,1H),3.85(q,J=6.1,4.7Hz,2H),3.24(s,2H),1.59(p,J=6.8Hz,2H),0.99-0.65(m,3H); 13 C NMR(126MHz,CDCl3)δ157.1,135.8,131.7,127.9,124.6,122.5,120.5,109.9,103.9,100.9,70.04,49.6,49.4,49.2,49.1,48.9,48.7,48.57,22.3,10.2ppm。

[0179] NUCC-0201027: 1 H NMR(500MHz,CDCl3)δ7.88(d,J=5.1Hz,3H),7.55(d,J=8.6Hz,1H),7.35-7.16(m,1H),7.03-6.80(m,3H),6.80-6.66(m,2H),6.61(d,J=8.7Hz,1H),4.11(t,J=6.5 Hz,2H),3.74(d,J=1.5 Hz,3H),2.84(t,J=6.6 Hz,2H)ppm; 13 C NMR(126 MHz,CDCl3)δ158.2,157.1,131.6,129.8,129.7,128.2,124.5,122.4,115.6,113.7,109.3,101.5,69.7,55.2,34.6 ppm。

[0180] NUCC-0201025: 1 H NMR(500 MHz,CDCl3)δ8.00(d,J=39.3 Hz,3H),7.43-7.29(m,1H),7.29-7.14(m,2H),7.04-6.93(m,2H),6.86-6.75(m,1H),6.70(s,1H),5.28(s,1H),4.28(t,J=6.6Hz,2H),3.94(s,2H),3.01(q,J=6.6 Hz,2H)ppm; 13C NMR(126MHz,CDCl3)δ157.8,156.9,151.4,142.1,141.8,139.5,136.3,136.2,134.7,132.4,132.3,132.04,131.7,131.5,131.4,131.2,130.1,130.05,128.4,128.4,128.1,126.6,124.4,122.3,122.2,121.5,121.5,121.5,120.05,115.7,115.4,109.5,109.3,105.4,104.7,104.2,101.6,69.3,69.1,37.7,34.9,34.8 ppm。

[0181] NUCC-200736: 1 H NMR(500 MHz,CDCl3)δ7.82(d,J=1.8 Hz,1H),7.63(dd,J=8.0,1.8 Hz,1H),7.47(d,J=8.0 Hz,1H),7.28-7.20(m,3H),7.11(dd,J=8.5,3.5 Hz,2H),6.68(d,J=8.5 Hz,1H),6.55(s,1H),5.04(d,J=2.6 Hz,2H),3.81(s,3H)ppm。

[0182] NUCC-200723: 1 H NMR(500 MHz,CDCl3)δ13.15(s,1H),7.96-7.81(m,1H),7.72(d,J=8.9 Hz,1H),7.13(d,J=8.5 Hz,1H),6.66(d,J=8.5 Hz,1H),6.59(s,1H),6.52(d,J=8.9 Hz,1H),3.84(s,3H)ppm。

[0183] NUCC-200576: 1 H NMR(500 MHz,MeOH-d4)δ7.49-7.44(m,2H),7.42-7.37(m,2H),7.34-7.30(m,1H),7.30-7.24(m,1H),7.13(d,J=8.4 Hz,1H),7.05(s,1H),6.91(d,J=2.3Hz,2H),5.07(s,2H),4.95(s,1H)ppm。

[0184] NUCC-200495: 1H NMR(500 MHz,CDCl3)δ7.96(d,J=1.7 Hz,2H),7.90(s,1H),7.50(d,J=8.6 Hz,1H),6.97-6.90(m,1H),6.60(d,J=8.6 Hz,1H)ppm。

[0185] NUCC-198407: 1 H NMR(500 MHz,CDCl3)δ7.45-7.33(m,4H),7.13(d,J=8.5 Hz,1H),6.59(d,J=8.6 Hz,1H),6.48(s,1H),5.15(s,2H),3.79(s,3H)ppm。

[0186] NUCC-198399: 1 H NMR(500 MHz,CDCl3)δ7.79-7.72(m,2H),7.68(dt,J=7.8,1.4Hz,1H),7.66-7.59(m,1H),7.35-7.32(m,2H),7.24(d,J=8.6 Hz,1H),7.17(t,J=6.9 Hz,2H),6.74(t,J=5.7 Hz,1H),6.59(s,1H),5.07(s,2H),3.87(s,3H)ppm。

[0187] NUCC-198398: 1 H NMR(500 MHz,CDCl3)δ7.78(s,1H),7.75-7.66(m,2H),7.61(t,J=8.5 Hz,2H),7.32(d,J=8.5 Hz,2H),7.13(t,J=12.8 Hz,2H),6.93(s,1H),6.72(d,J=8.8 Hz,1H),5.06(s,2H)ppm。

[0188] NUCC-198394: 1 H NMR(500 MHz,CDCl3)δ8.00(d,J=8.3 Hz,1H),7.62(d,J=8.6Hz,1H),7.55(d,J=8.3 Hz,1H),7.38(s,1H),7.14(d,J=8.3 Hz,1H),6.88(s,1H),6.74(d,J=8.9Hz,1H),5.07(s,2H)ppm。

[0189] NUCC-198391: 1H NMR(500 MHz,CDCl3)δ7.79(t,J=8.4 Hz,1H),7.59(d,J=8.4Hz,2H),7.31(d,J=8.4 Hz,1H),7.12(t,J=10.8 Hz,2H),6.93(s,1H),6.76-6.65(m,1H),5.06(s,2H)ppm。

[0190] NUCC-198363: 1 H NMR(500 MHz,CDCl3)δ7.64(d,J=8.7 Hz,2H),7.50-7.43(m,2H),7.41-7.35(m,1H),7.31-7.26(m,4H),7.15(d,J=8.5 Hz,1H),6.86(s,1H),5.07(s,2H)ppm。

[0191] NUCC-196362: 1 H NMR(500 MHz,CDCl3)δ7.94(s,2H),7.85(s,1H),7.58(d,J=8.7Hz,2H),7.27(d,J=2.0 Hz,1H),7.13(d,J=8.3 Hz,2H),6.95(s,1H),6.70(d,J=8.7 Hz,1H),5.03(s,2H)ppm。

[0192] NUCC-196361: 1 H NMR(500 MHz,CDCl3)δ7.88(s,2H),7.84(s,1H),7.28-7.16(m,3H),7.11(d,J=8.1 Hz,2H),6.73(d,J=8.5 Hz,1H),6.56(s,1H),5.01(s,2H),3.80(s,3H)ppm; 13 C NMR(126 MHz,CDCl3)δ157.51,151.53,142.21,141.91,139.42,134.56,134.27,134.05,131.82,131.74,131.47,131.41,131.21,131.08,129.16,128.92,128.82,128.33,128.21,124.42,122.26,122.19,121.62,120.05,115.89,115.77,109.80,107.55,105.51,105.30,69.88ppm。

[0193] NUCC-196344: 1 H NMR (500MHz, CDCl3) δ7.53 (d, J=8.7Hz, 1H), 7.45 (d, J=8.3Hz, 1H), 7.35 (d, J=7.7Hz, 2H), 7.26 (t, J=6.9Hz, 3H) , 7.21 (d, J=7.7Hz, 1H), 7.11 (d, J=8.3Hz, 2H), 6.78 (s, 1H), 6.66 (d, J=8.8Hz, 1H), 5.02 (s, 2H), 2.43 (s, 3H)ppm.

[0194] C. Synthesis Method C Synthesis method C

[0195] Step 1. Add 9 mL of dichloromethane to a solution of 1-(2,4-dihydroxyphenyl)ethyl ketone (0.92 g, 6.05 mmol) and pyridinium p-toluenesulfonate (0.061 g, 0.242 mmol), and then add 3,6-dihydro-2H-pyran (1.655 mL, 18.14 mmol, 1 equivalent). Stir the resulting solution at rt for 3 h. Stop the reaction by adding 9 mL of saturated aqueous NaHCO3. Separate the layers, extracting the aqueous layer with (2 x 10) mL of dichloromethane. Dry the combined organic layers with Na2SO4, filter, and concentrate. Then, dissolve the resulting solid in 50 mL of EtOH and add ethyl oxalate (18.15 mmol, 3 equivalents). Add the resulting solution dropwise to a suspension of sodium ethoxide (30.3 equivalents) in 10 mL of ethanol. After the addition, heat the reaction system at 90 °C for 30 min. The reaction system was cooled, and 50 mL of DCM and 20 mL of 3M HCl were added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried with Na₂SO₄, filtered, and concentrated. The resulting yellow solid was then dissolved in 50 mL of a 1:1 dichloromethane:THF mixture, and pTsOH (0.6 mmol, 1 equivalent) was added. The mixture was stirred at RT for 1.5 h. The reaction system was then concentrated directly under reduced pressure. Finally, pyridine (24 mmol, 4 equivalent) was added to a solution of the resulting solid, iodine (24 mmol), and CHCl₃ in 75 mL. The resulting solution was stirred at room temperature for 16 h. Then, 75 mL of saturated Na₂S₂O₃ aqueous solution was added, and the mixture was stirred for 1 h. The organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (3 x 60 mL). The combined organic layers were washed with brine and dried with anhydrous Na₂SO₄. The solvent was then removed under reduced pressure, and the residue was ground several times with diethyl ether.

[0196] Step 2. The suspension of 2-carbonyl-chromone (3 mmol), haloalkane (3.6 mmol, 1.2 equivalents), and K₂CO₃ (6 mmol) in 30 mL of acetone was heated at 60 °C for 16 h. The suspension was filtered through a funnel, and the solvent was removed under reduced pressure. The residue was ground together with water and dried under reduced pressure until dry.

[0197] Step 3. Effervesce the suspension of the above-mentioned alkylated chromone (0.34 mmol, 1 equivalent) with the corresponding boric acid (0.37 mmol, 1.1 equivalent), Na₂CO₃ (0.68 mmol, 2 equivalent), and Pd(dppf)Cl₂ (0.026 mmol, 0.08 equivalent) in a 3.5 mL mixture of 1:2:6 EtOH:water:toluene for 10 minutes under nitrogen. Then cover the flask and heat the mixture at 90 °C for 2 h. Cool the dark solution to room temperature and dilute with EtOAc. Separate the organic layer and extract the aqueous phase with EtOAc (3 x 3 mL). Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Remove the solvent under reduced pressure and purify the residue by silica gel chromatography.

[0198] Step 4. The solution of the above-mentioned chromone (0.2 mmol, 1 equivalent) and the desired hydrazine (0.6 mmol, 3 equivalent) in 2 mL of EtOH was heated at 70 °C for 45 minutes. The solution was cooled to room temperature and concentrated. The solid product (n-hexane / ethyl acetate = 5:1-1:1) was directly purified by silica gel chromatography to obtain the desired pyrazole.

[0199] Step 5. Add one drop of 10% NaOH aqueous solution to a solution of ethyl-esterpyrazole (0.1 mmol, 1 equivalent) in 0.5 mL of a 1:1 THF:water mixture, and stir at RT for 24 h. Concentrate the reaction system to dryness. Then dissolve the resulting solid in 1 mL of LMF and TSTU (0.1 mmol, 1 equivalent), add DIPEA (0.2 mmol), and stir the solution at RT for 20 min. Subsequently, add amine (0.2 mmol), and stir at RT for 30 min. Purify the reaction system directly by preparative reversed-phase HPLC.

[0200] Example

[0201] NUCC-201224: 1H NMR (500MHz, CDCl3) δ11.00 (s, 1H), 7.96 (d, J=1.6Hz, 2H), 7.79 (s, 1H), 7.46 (d, J=8.7Hz, 1H), 7.32-7.18 (m, 2H), 7.13 (d, J =8.4Hz, 2H), 6.74 (s, 1H), 6.62 (d, J = 8.7Hz, 1H), 6.09 (q, J = 4.9Hz, 1H), 4.99 (s, 2H), 4.14 (s, 3H), 2.99 (d, J = 4.9Hz, 3H) ppm.

[0202] NUCC-200973: 1 H NMR (500MHz, CDCl3) δ7.90 (s, 2H), 7.72 (s, 1H), 7.52 (d, J = 8.6Hz, 1H), 7.27 (s, 1H), 7.18 (d , J=8.0Hz, 2H), 7.07 (d, J=8.5Hz, 2H), 7.03 (s, 1H), 6.60 (d, J=8.6Hz, 1H), 4.95 (s, 2H)ppm.

[0203] NUCC-200558: 1 H NMR (500MHz, CDCl3) δ10.90 (s, 1H), 7.77 (t, J=1.6Hz, 1H), 7.70 (dt, J=7.8, 1.6Hz, 1H), 7.60 (dt, J=7.8, 1.6Hz, 1H), 7.53-7 .43 (m, 2H), 7.27 (d, J=8.3Hz, 2H), 7.12 (d, J=8.3Hz, 2H), 6.81 (s, 1H), 6.60 (d, J=8.7Hz, 1H), 5.01 (s, 2H), 4.15 (s, 3H)ppm.

[0204] D. Synthesis Method D Synthesis method D

[0205] Step 1. In a suitably sized vial, add the substituted phenol (1 equivalent), aryl / alkyl chloride (1.1 equivalent), and K₂CO₃ (3 equivalent) in dry acetone, and stir overnight at 60°C. Upon completion, evaporate the solvent and suspend the residue in EtOAc (10 mL). Wash the organic fraction with H₂O (2 x 10 mL). Extract the combined aqueous fractions with EtOAc (10 mL). Wash the combined organic fractions with brine, dry with Na₂SO₄, and evaporate to obtain the crude residue. Use the residue for the next step without further purification.

[0206] Step 2. In a suitably sized vial, add (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (1 equivalent), the product from Step 1 (1 equivalent), Pd(dppf)2Cl2 (0.05 equivalent), and Na2CO3 (3 equivalent) from a dioxane:H2O (1:1) mixture. Purge the vial with N2 for 1 min and stir at 100°C for 1 h. Upon completion, cool the reaction mixture to room temperature and pass it through a silica gel pad using DCM:MeOH (10:1). Evaporate the solvent to obtain a crude residue. Purification of the crude product by preparative HPLC did not yield the desired product. For example, NUCC-0200813: 1 H NMR (500MHz, CDCl3) δ7.32 (s, 1H), 7.28-7.19 (m, 4H), 7.12 (s, 1H), 7.05 (d, J=8.4Hz, 1H), 7.01 (d, J=2.8Hz, 1H), 6.77 (dd, J=8.5, 2.8Hz, 1H), 4.94 (s, 2H), 4.34 (s, 2H), 3.86 (s, 3H); 13 C NMR (126MHz, CDCl3) δ158.7, 140.9, 135.3, 133.9, 132.5, 131.9, 128.8, 121.7, 118.9, 114.3, 113.7, 69.3, 63.3, 39.6.

[0207] Step 3. In a suitable vial, add the product of Step 2 (1 equivalent) and NaBH4 (1.2 equivalent) in methanol, and stir at room temperature for 7 h. Upon completion, concentrate the reaction system and suspend it in H2O. Extract the suspension with EtOAc (3 x 3 mL), evaporate the combined organic fractions to obtain a crude residue, and purify it by preparative HPLC.

[0208] Example

[0209] NUCC-0200813: Preparative HPLC conditions (40-80%, 5 min, 50 x 30 mm, Rt = 3.74 min). 1 H NMR (500MHz, CDCl3) δ7.32 (s, 1H), 7.30-7.18 (m, 4H), 7.10-6.95 (m, 2H), 6.77 (dd, J=8.5, 2.8Hz, 1H), 4.94 (s, 2H), 4.34 (s, 2H), 3.86 (s, 3H)ppm; 13C NMR (126MHz, CDCl3) δ158.7, 140.9, 135.3, 133.8, 132.5, 131.9, 128.8, 121.73, 118.9, 114.3, 113.7, 69.3, 63.3, 39.6ppm.

[0210] Step 4. In an appropriately sized vial, add the product from Step 2 (1 equivalent) and NBS (5 equivalents) in anhydrous DMF, and stir the reagents at room temperature for 3 days. Upon completion, stop the reaction with water (4 mL) and extract with EtOAc (3 x 3 mL). Dry the combined organic fractions and purify the residue using a Biotage (5:1 Hex / EtOAc; 10 g column). Collected fractions: 11-14, e.g., NUCC-0200979. 1 H NMR (500MHz, CDCl3) δ7.42-7.34 (m, 6H), 7.31 (dd, J=8.7, 2.6Hz, 1H), 5.11 (s, 2H), 3.82 (s, 3H); 13 C NMR (126MHz, CDCl3) δ159.7, 140.2, 140.1, 139.8, 134.6, 133.6, 133.3, 129.1, 128.8, 123.1, 120.1, 119.4, 119.3, 116.3, 115.1, 93.7, 70.0, 38.8.

[0211] Step 5. In a suitably sized vial, add the product from Step 2 in MeOH (1 equivalent), H₂O₂ (30% aqueous solution, 1 equivalent), and Na₂CO₃ (3 equivalents), and stir overnight at room temperature. Upon completion, evaporate the solvent, suspend the residue in water (1 mL), and extract with EtOAc (3 x 1 mL). Evaporate the combined organic fractions to obtain the crude product, which is purified by preparative HPLC. For example, NUCC-0200816: 1 H NMR (500MHz, CDCl3) δ7.33 (d, J=2.7Hz, 1H), 7.24 (s, 4H), 7.19-7.04 (m, 2H), 6.99 (dd , J=8.5, 2.7Hz, 1H), 6.40 (s, 1H), 5.47 (s, 1H), 5.23 (s, 1H), 4.98 (s, 2H), 3.58 (s, 3H); 13 C NMR (126MHz, CDCl3) δ168.6, 159.7, 142.6, 136.6, 134.4, 134.2, 132.8, 128.9, 128.8, 119.3, 117.8, 115.1, 104.9, 69.6, 37.5.

[0212] E. Synthesis Method E Synthesis method E

[0213] Step 1. Add 9 mL of dichloromethane to a solution of 1-(2,4-dihydroxyphenyl)acetone (0.92 g, 6.05 mmol, 1 equivalent) and pyridinium p-toluenesulfonate (0.061 g, 0.242 mmol, 0.04 equivalent), and then add 3,6-dihydro-2H-pyran (1.655 mL, 18.14 mmol, 3 equivalents). Stir the resulting solution at rt for 3 h. Stop the reaction by adding 9 mL of saturated NaHCO3 aqueous solution. Separate the layers, extracting the aqueous layer with dichloromethane (2 x 10 mL). Dry the combined organic layers. Dissolve the pale red oily-solid substance in DMF-DMA (9.1 mmol) and heat at 95 °C for 3 h. Then cool and concentrate under reduced pressure. The obtained solid was then dissolved in 50 mL of a 1:1 dichloromethane:THF mixture, and pTsOH (0.6 mmol, 1 equivalent) was added. The mixture was stirred at RT for 1.5 h. The reaction system was then concentrated directly under reduced pressure. Finally, pyridine (24 mmol, 4 equivalent) was added to a solution of the obtained solid, iodine (24 mmol, 4 equivalent), and chlorine in 75 mL of CHCl3. The resulting solution was stirred at room temperature for 16 h. Then, 75 mL of saturated Na2S2O3 aqueous solution was added, and the resulting mixture was stirred for 1 h. The organic layer was separated, and the aqueous phase was extracted with CH2Cl2 (3 x 60 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure, and the residue was ground several times with diethyl ether.

[0214] Step 2. A suspension of chromone (3 mmol, v), haloalkane (3.6 mmol, 1.2 equivalents), and K₂CO₃ (6 mmol) in 30 mL of acetone was heated at 60 °C for 16 h. The reaction system was filtered through a funnel, and the solvent was removed under reduced pressure. The crude product was ground together with water and dried under reduced pressure until dry.

[0215] Step 3. Effervesce the above-mentioned alkylated chromone (0.34 mmol, 1 equivalent) with the corresponding boric acid (0.37 mmol, 1.1 equivalent), Na₂CO₃ (0.68 mmol, 2 equivalent), and Pd(dppf)Cl₂ (0.026 mmol, 0.08 equivalent) in a 3.5 mL 1:2:6 EtOH:water:toluene mixture for 10 minutes under nitrogen atmosphere. Then, cap the flask and heat the mixture at 90 °C for 2 h. Cool the dark solution to room temperature and dilute with EtOAc. Separate the organic layer and extract the aqueous phase with EtOAc (3 x 3 mL). Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Remove the solvent under reduced pressure and purify the residue by silica gel chromatography.

[0216] Step 4. The solution of the above-mentioned chromone (0.2 mmol, 1 equivalent) and the desired hydrazine (0.6 mmol, 3 equivalent) in 2 mL of EtOH was heated at 70 °C for 45 minutes. The solution was cooled to room temperature and concentrated. The solid product (n-hexane / ethyl acetate = 5:1-1:1) was directly purified by silica gel chromatography to obtain the desired pyrazole.

[0217] Example

[0218] NUCC-198359: 1 H NMR (500MHz, CDCl3) δ7.45 (s, 1H), 7.35 (s, 3H), 7.00 (s, 2H), 6.82 (d, J=8.8Hz, 1H), 6.62 (d, J =2.6Hz, 1H), 6.22 (dd, J=8.8, 2.6Hz, 1H), 4.99 (s, 3H), 2.38 (s, 3H), 2.03 (d, J=6.1Hz, 6H) ppm.

[0219] NUCC-198322: 1 H NMR (500MHz, CDCl3) δ7.80 (s, 1H), 7.51 (dt, J=9.0, 4.5Hz, 1H), 7.40-7.37 (m, 4H) , 7.32 (d, J=7.3Hz, 1H), 6.66 (d, J=2.6Hz, 1H), 6.52-6.41 (m, 3H), 5.05 (s, 2H)ppm.

[0220] NUCC-198318: 1H NMR (500MHz, CDCl3) δ7.87 (s, 1H), 7.85 (s, 2H), 7.77 (s, 1H), 7.38 (s, 4H), 6.95 ( d, J=8.7Hz, 1H), 6.69 (d, J=2.6Hz, 1H), 6.34 (dd, J=8.7, 2.6Hz, 1H), 5.04 (s, 2H).

[0221] NUCC-196350: 1 H NMR (500MHz, CDCl3) δ7.61 (s, 1H), 7.45 (s, 1H), 7.36 (s, 1H), 7.33 (s, 3H), 7.31-7.28 (m, 2 H), 7.08-7.01 (m, 2H), 6.62 (d, J=2.6Hz, 1H), 6.29 (dd, J=8.7, 2.6Hz, 1H), 4.99 (s, 2H)ppm.

[0222] NUCC-196348: 1 H NMR (500MHz, CDCl3) δ7.41-7.33 (m, 2H), 7.31-7.06 (m, 7H), 6.66 (d, J=8.6Hz, 1H), 6.51 (s, 1H), 5.02 (s, 2H), 3.82 (s, 3H)ppm.

[0223] F. Synthesis Method F Synthesis method F

[0224] Step 1. Add 4.02 mL of etherified boron trifluoride (ORON, 31.7 mmol, 3 equivalents) to a mixture of 2-phenylacetic acid derivative (10.58 mmol, 1 equivalent) and resorcinol (1.165 g, 10.58 mmol, 1 equivalent). Seal the vial and stir at 90 °C for 1.5 h. Cool the reaction mixture to RT. Partition the resulting solid between 20 mL of water and 20 mL of dichloromethane. Separate the layers, extracting the aqueous layer with dichloromethane (3 x 10 mL). Dry the combined organic layers with Na₂SO₄, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography.

[0225] Step 2. The suspension of O-phenoxyacetophenone (1 mmol) with TFFA (5 equivalents) and pyridine (5 equivalents) was heated at 120 °C for 4 h. It was then cooled to rt. In some cases, the product was precipitated; in others, water was added, followed by extraction with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography.

[0226] Step 3. The suspension of chromone (0.5 mmol, 1 equivalent), K2CO3 (1 mmol), and haloalkane (0.6 mmol) in 5 mL of acetone was heated at 60 °C for 16 h. The reaction system was filtered through a funnel, and the solvent was removed under reduced pressure. The crude product was ground together with water and dried under reduced pressure until dry.

[0227] Step 4. The solution of the above-mentioned O-alkylated chromone (0.2 mmol) and the desired hydrazine (0.6 mmol, 3 equivalents) in 2 mL of LEtOH was heated at 70 °C for 45 min. The solution was cooled to room temperature and concentrated. The solid product (n-hexane / ethyl acetate = 5:1-1:1) was directly purified by silica gel chromatography to obtain the desired pyrazole.

[0228] Example

[0229] NUCC-198309: 1 H NMR (500MHz, CDCl3) δ7.38-7.33 (m, 5H), 7.00-6.84 (m, 4H), 6.55 (s, 1H), 6.35 (s, 1H), 5.00 (s, 2H), 3.81 (s, 3H)ppm.

[0230] NUCC-198295: 1 H NMR (500MHz, CDCl3) δ7.44 (d, J=2.2Hz, 3H), 7.38-7.31 (m, 6H), 6.89 (s, 1H), 6.55 (s, 1H), 6.32 (s, 1H), 5.00 (s, 2H)ppm.

[0231] NUCC-196340: 1 H NMR (500MHz, CDCl3) δ7.97 (s, 1H), 7.45 (d, J=9.0Hz, 1H), 7.37-7.28 (m, 2H), 7.18 (d, J=8.7Hz, 2H), 6.86 (d, J=8.7Hz, 2H), 6.45 (d, J=2.6Hz, 1H), 6.37 (dd, J=9.0, 2.6Hz, 1H), 5.92 (s, 1H), 5.01 (s, 2H), 3.78 (s, 3H)ppm.

[0232] NUCC-196282: 1H NMR (500MHz, CDCl3) δ7.34-7.28(m, 4H), 6.94(s, 1H), 6.92-6.84(m, 2H), 6.79(d, J=1.8Hz, 1H), 6.52(s, 1H), 6.31(s, 1H), 4.97(s, 2H), 3.92(s, 3H), 3.78(s, 3H)p.

[0233] G. Synthesis Method G Synthesis method G

[0234] Step 1. Add sodium 2,2,2-trifluoroacetate (9.84 g, 72.36 mmol, 2.2 equivalents) to a suspension of 1-(2,4-dihydroxyphenyl)ethyl-1-one (5.00 g, 32.89 mmol, 1 equivalent) in trifluoroacetic anhydride (18.50 mL, 131.56 mmol, 4 equivalents) in an autoclave. Cap the system and stir at 110 °C for 24 h. Cool the reaction system to approximately 70 °C and dilute with 200 mL of EtOAc. Neutralize the mixture by adding saturated K₂CO₃ aqueous solution until no more foaming is observed. Separate the layers and extract the aqueous phase with EtOAc (3 x 150 mL). Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Then concentrate the solution to 100–150 mL of EtOAc. The flask was then capped and kept at room temperature for 1-2 days to obtain a solid. The solid was filtered, dried under vacuum, and 4.09 g of pure 1 was obtained as a white solid, with a yield of 54%.

[0235] Then, under a nitrogen atmosphere, Tf₂O (2.20 mL, 13.06 mmol, 1.5 equivalent) was added dropwise to an ice bath solution of pyridine (2.81 mL, 34.8 mmol, 4 equivalent) in 18 mL of DCM for 15 min. The mixture was then stirred from 0 °C to room temperature for 16 h. The reaction was stopped by adding 15 mL of water. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solvent was then removed under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 10:1–4:1) to give compound 2 as a yellow solid, 95% yield (3.0 g): mp 46–48 °C. 1 H NMR (500MHz, DMSO-d6) δ 8.32-8.20 (m, 2H), 7.74 (dd, J=8.8, 2.4Hz, 1H), 7.17 (s, 1H)ppm. 13C NMR (126MHz, DMSO-d6) δ175.4, 155.6, 152.4, 151.4 (q, 2 J (C, F) = 38.8Hz), 128.2, 123.7, 120.1, 118.5 (q, 1 J(C,F) = 274.7 Hz, 112.9, 111.5, 111.4 ppm. HRMS (ESI): Calculated mass value C 11 H5F6O5S + [M+H] + =362.9756, measured value =362.9758.

[0236] Step 2. To obtain different Pd-catalyzed coupling products at the 7-position of 2-CF3-chromone, different conditions were followed:

[0237] Condition A: Aniline Coupling: A suspension of chromone-trifluoromethanesulfonate (150 mg, 0.41 mmol, 1 equivalent) with Cs₂CO₃ (202 mg, 0.62 mmol, 1 equivalent), BINAP (25 mg, 0.04 mmol, 0.1 equivalent), and PdOAc₂ (4.5 mg, 0.02 mmol, 0.05 equivalent) in 4 mL toluene was bubbled for 10 minutes under nitrogen. The flask was then capped, and the mixture was heated at 90 °C for 16 h. The dark solution was cooled to room temperature and diluted with 5 mL EtOAc and 5 mL water. The organic layer was separated, and the aqueous phase was extracted with EtOAc₂ (3 x 5 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solvent was then evaporated under reduced pressure, and the residue was purified by silica gel chromatography.

[0238] Condition B: Phenol Coupling: A suspension of chromone-trifluoromethanesulfonate (150 mg, 0.41 mmol, 1 equivalent) with K₂CO₃ (113 mg, 0.82 mmol, 2 equivalents), John Phos (12 mg, 0.04 mmol, 0.1 equivalents), and Pd₂dba₃ (19 mg, 0.02 mmol, 0.05 equivalents) in 4 mL toluene was bubbled for 10 minutes under nitrogen. The flask was then capped, and the mixture was heated at 90 °C for 16 h. The dark solution was cooled to room temperature and diluted with 5 mL EtOAc and 5 mL water. The organic layer was separated, and the aqueous phase was extracted with EtOAc₂ (3 x 5 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solvent was then evaporated under reduced pressure, and the residue was purified by silica gel chromatography.

[0239] Condition C: Boric acid coupling to biarylchromone: A suspension of chromone-trifluoromethanesulfonate (150 mg, 0.41 mmol, 1 equivalent) with the corresponding boric acid (0.46 mmol, 1.1 equivalent), Na₂CO₃ (87 mg, 0.82 mmol, 2 equivalent), and Pd(dppf)Cl₂ (23 mg, 0.03 mmol, 0.08 equivalent) in 4 mL of a 1:2:6 EtOH:water:toluene mixture was bubbled for 10 min under nitrogen. The flask was then capped and the mixture was heated at 90 °C for 20 min. The dark solution was cooled to room temperature and diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc₂ (3 x 3 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solvent was then evaporated under reduced pressure, and the residue was purified by silica gel chromatography.

[0240] Step 3. The solution of the above-mentioned 7-functionalized chromone (0.2 mmol, 1 equivalent) and the desired hydrazine (0.6 mmol, 3 equivalent) in 2 mL of EtOH was heated at 70 °C for 45 min. The solution was cooled to room temperature and concentrated. The solid product (n-hexane / ethyl acetate = 5:1-1:1) was directly purified by silica gel chromatography to obtain the desired pyrazole.

[0241] Example

[0242] NUCC-201223: 1 H NMR (500MHz, CDCl3) δ10.62 (s, 1H), 7.92 (d, J=1.7Hz, 2H), 7.81 (s, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.23-7.19 (m, 2H), 6.98 (s, 1H), 6.86-6.77 (m, 2H), 6.61 (d, J=8.7Hz, 1H) ppm.

[0243] NUCC-200721: 1 H NMR (500MHz, CDCl3) δ7.46 (d, J=8.4Hz, 1H), 7.31 (d, J=8.7Hz, 1H), 7.20 (d, J=2.7Hz, 1H), 6.92 (dd, J=8.7, 2.7Hz, 1H), 6.84 (s, 1H), 6.62 (d, J=7.7Hz, 2H), 5.78 (s, 1H)ppm.

[0244] NUCC-200681: 11H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.7 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 2.57 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H) ppm.

[0245] NUCC-200679: 1 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.6 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.01 - 6.97 (m, 2H), 6.88 (s, 1H), 6.60 (dd, J = 8.5, 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H) ppm.

[0246] NUCC-200559: 1 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.05 (q, J = 9.1 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.87 (dd, J = 8.7, 2.4 Hz, 1H), 6.77 (d, J = 8.2 Hz, 2H), 6.56 (dd, J = 8.5, 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 5.72 (s, 1H) ppm.

[0247] NUCC-200492: 1 1H NMR (500 MHz, CDCl3) δ 7.28 - 7.25 (m, 2H), 7.09 - 7.06 (m, 2H), 7.06 - 7.02 (m, 1H), 6.61 (d, J = 7.7 Hz, 2H), 6.53 (s, 1H), 3.81 (s, 3H) ppm.

[0248] NUCC-200491: 1 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H), 7.10 - 6.97 (m, 2H), 6.81 (s, 1H), 6.62 (dq, J = 5.3, 2.2 Hz, 2H), 5.80 (s, 1H) ppm.

[0249] H. Synthetic Method H Synthesis method H

[0250] Step 1. Add sodium 2,2,2-trifluoroacetate (9.84 g, 72.36 mmol, 2.2 equivalents) to a suspension of 1-(2,4-dihydroxyphenyl)ethyl-1-one (5.00 g, 32.89 mmol, 1 equivalent) in trifluoroacetic anhydride (18.50 mL, 131.56 mmol, 4 equivalents) in an autoclave. Cap the system and stir at 110 °C for 24 h. Cool the reaction system to approximately 70 °C and dilute with 200 mL of EtOAc. Neutralize the mixture by adding saturated K₂CO₃ aqueous solution until no more foaming is observed. Separate the layers and extract the aqueous phase with EtOAc (3 x 150 mL). Wash the combined organic layers with brine and dry with anhydrous Na₂SO₄. Then concentrate the solution to 100–150 mL of EtOAc. The flask was then capped and kept at room temperature for 1-2 days to obtain a solid. The solid was filtered, dried under vacuum, and 4.09 g of pure 1 was obtained as a white solid, with a yield of 54%.

[0251] Step 2. A suspension of 7-hydroxy-2-(trifluoromethyl)-4H-chromen-4-one (1 g, 2.8 mmol, 1 equivalent), a haloalkane (3.4 mmol, 1.2 equivalent), and K₂CO₃ (0.77 g, 5.6 mmol, 2 equivalent) in 5 mL of acetone was heated at 60 °C for 16 h. The reaction system was filtered through a funnel, and the solvent was removed under reduced pressure. The crude product was ground together with water and dried under reduced pressure until dry.

[0252] Step 3.

[0253] Synthesis of pyrazole: A solution of the above-mentioned chromone (0.2 mmol, 1 equivalent) in 2 mL of EtOH and the desired hydrazine (0.6 mmol, 3 equivalent) was heated at 70 °C for 45 min. The solution was cooled to room temperature and concentrated. The solid product (n-hexane / ethyl acetate = 5:1-1:1) was directly purified by silica gel chromatography to give the desired pyrazole.

[0254] Example

[0255] NUCC-198314: 1 H NMR (500MHz, CDCl3) δ7.12 (s, 1H), 6.97 (d, J=8.5Hz, 1H), 6.51 (dd, J=8.5, 2.4Hz, 1H), 6.46 (d, J=2.4Hz, 1H), 6.41 (s, 1H), 4.92 (s, 2H), 3.67 (s, 3H)ppm.

[0256] Synthesis of pyrimidines. A solution of the above-mentioned chromone (0.2 mmol, 1 equivalent) in 10 mL of EtOH with the desired benzoimide (0.26 mmol, 1.3 equivalent) and potassium hydroxide (0.6 mmol, 3 equivalent) was heated at 80 °C for 14 h. The solution was diluted with 5 mL of water and extracted with 3 x 15 mL EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The solid product (n-hexane / ethyl acetate = 5:1–1:1) was directly purified by silica gel chromatography to give the desired pyrimidine.

[0257] Example

[0258] NUCC-0200500: 1 H NMR (500MHz, CDCl3) δ 8.80-8.73 (m, 2H), 8.07 (s, 1H), 7.95 (s, 1H), 7.81 (d, J=8.9Hz, 1H), 7.37 (s, 4H), 6.69-6.59 (m, 2H), 5.10 (s, 2H)ppm.

[0259] I. Synthesis Method I Synthesis Method I (PAL)

[0260] Steps 1-4 are the same as those in synthesis method B described above.

[0261] Step 5. In a 100 mL round-bottom flask, dimethyl malonate (1.1 equivalents), propargyl bromide (1 equivalent), and K₂CO₃ (3 equivalents) in dry acetone are stirred at room temperature for 36 h. The oxidation is quenched by adding saturated NH₄Cl solution, and the mixture is extracted with DCM (3 times). The combined organic layers are washed with H₂O (2 times), dried with Na₂SO₄, and the solvent is evaporated under reduced pressure to give a yellow oily substance that converts to a solid upon standing. (Note: The conversion rate rf = 0.42 can be monitored by TLC: H:EtOAc: 5:1). The crude product is stirred with a MeOH solution of KOH (1 equivalent) at room temperature for 4 hours. Upon completion, the solvent is evaporated, the residue is suspended in H₂O, and washed with Et₂O (2 times). The aqueous fraction is acidified with HCl (2N, to pH 3) and extracted with EtOAc (2 times). The organic fraction is dried with Na₂SO₄ and evaporated to give a crude yellow oily substance. (Note: LCMS displays m / z = 157 and 174(+18)).

[0262] Step 6. In an appropriately sized vial, stir the product from Step 5 (1 equivalent), IBX-SO3K (1.5 equivalent), NaI (0.2 equivalent), and NaN3 (3.3 equivalent) in anhydrous DMSO in an ice-cold water bath for 5 min, then heat at 60°C for 2 h. Upon completion, quench the reaction mixture with saturated Na2S2O3 (25 mL) and extract with Et2O (2 x 25 mL). Wash the combined organic fractions with saturated NaHCO3 (2 x 25 mL) and dry with Na2SO4. Evaporate the organic fractions to give a yellow residue. Stir the crude product in THF:H2O (1:1) with LiOH (2 equivalent) at room temperature for 2 h. (Note: LCMS shows the dimer signal of SM and the product indicating completion of the reaction). Evaporate the solvent and use the crude product without any further purification for the next step.

[0263] Step 7. In appropriately sized vials, mix the product from Step 4 (1 equivalent), the product from Step 5 (1.5 equivalent), HATU (1.5 equivalent), and DIEA (4 equivalent) in anhydrous DCM at 30°C for 6 hours. Upon completion, evaporate the solvent to obtain the crude product. Purify the crude product by preparative HPLC.

[0264] Example

[0265] NUCC_0201698: Preparative HPLC: (25-90%, 50x30, C18, 50 mL / min, Rt = 4.3 min). UVmax = 222 nm 1 H NMR (500MHz, CDCl3) δ8.84 (dd, J=10.0, 1.9Hz, 3H), 8.16 (s, 1H), 8.02 (s, 2H), 7.50 (d, J=8.5Hz, 2H), 7.24 (s, 17H), 6.76 (d, J=8.6H z, 1H), 6.59 (s, 2H), 5.22 (s, 1H), 5.06 (s, 2H), 4.28 (dd, J=7.6, 4.1Hz, 1H), 3.83 (s, 3H), 3.09-2.75 (m, 3H), 2.23-2.06 (m, 1H)ppm.

[0266] NUCC-0201694: Preparative HPLC: (25-90%, 50x30, C18, 50 mL / min, Rt = 3.5 min). UVmax = 222 nm 11H NMR (500 MHz, CDCl3) δ 10.63 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.70 - 7.37 (m, 3H), 6.91 (s, 1H), 6.58 (d, J = 8.7 Hz, 1H), 6.41 (s, 1H), 4.13 - 3.85 (m, 4H), 3.27 (dq, J = 34.6, 6.8 Hz, 1H), 2.99 - 2.57 (m, 2H), 1.94 - 1.77 (m, 1H), 1.23 (s, 1H), 0.81 (s, 1H) ppm.

[0267] NUCC - 0201695: Preparative HPLC: (25 - 90%, 50x30, C18, 50 mL / min, Rt = 4.5 - 5 min). UVmax = 222 nm 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 2.0 Hz, 1H), 7.68 - 7.48 (m, 2H), 7.19 (d, J = 8.6 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.55 (s, 1H), 6.43 (s, 1H), 5.09 (s, 1H), 4.04 (dt, J = 30.2, 6.5 Hz, 3H), 3.82 (s, 3H), 3.27 (dt, J = 36.6, 6.8 Hz, 2H), 2.96 - 2.82 (m, 1H), 2.77 - 2.62 (m, 1H), 2.05 (t, J = 2.7 Hz, 1H), 1.98 - 1.81 (m, 2H) ppm.

[0268] NUCC - 0201696: Preparative HPLC: (25 - 90%, 50x30, C18, 50 mL / min, Rt = 4.6 min). UVmax = 222 nm 1 1H NMR (500 MHz, CDCl3) δ 8.85 (dd, J = 9.8, 2.1 Hz, 3H), 8.06 (d, J = 2.2 Hz, 1H), 7.24 (s, 13H), 6.69 (d, J = 8.6 Hz, 1H), 6.59 (s, 1H), 6.45 (s, 1H), 5.27 (s, 1H), 4.19 - 3.93 (m, 3H), 3.84 (s, 3H), 3.28 (ddd, J = 47.0, 13.7, 6.8 Hz, 2H), 2.88 (ddd, J = 17.2, 4.3, 2.6 Hz, 1H), 2.69 (ddd, J = 17.1, 7.2, 2.7 Hz, 1H), 1.90 (dt, J = 7.7, 3.9 Hz, 2H) ppm.

[0269] NUCC-0210697: Preparative HPLC: (25-90%, 50x30, C18, 50 mL / min, Rt = 3.8-4.1 min). UVmax = 222 nm 1 H NMR (500MHz, CDCl3) δ9.03-8.72 (m, 2H), 8.13 (d, J=11.1Hz, 1H), 7.69-7.40 (m, 1H), 6.95 (d, J=5.2Hz, 1H), 6.69-6.43 (m, 2H), 4.07 (ddd, J=11.4, 8.8, 5.1Hz, 3H), 3.71-3.41 (m, 2H), 2.95-2.59 (m, 3H), 2.45 (dq, J=4.9, 2.4Hz, 1H), 2.04-1.88 (m, 1H)ppm.

[0270] J. Synthesis Method J Synthesis method J (PTOTAC)

[0271] Steps 1-4 are the same as those in synthesis method B described above.

[0272] Step 5. In a suitably sized vial, azide-PEG carboxylic acid (1 equivalent) and thionyl chloride (39 equivalents) are stirred together at room temperature for 3 h. Upon completion (LCMS shows methyl ester indicating completion), excess thionyl chloride is evaporated to give crude acyl chloride. A solution of the product from Step 4 (1 equivalent) in anhydrous THF is added to the acyl chloride and TEA (5 equivalents), and the reaction mixture is stirred at 60 °C for 3 h. Upon completion, the mixture is filtered through a cotton pad and purified by preparative HPLC (50 x 30, C18, 50 mL / min, Rt. 3.3–3.6 min), dissolved without further purification for the coupling step (estimated yield).

[0273] Step 6. In an appropriately sized vial, stir the product from Step 5 (1 equivalent), CuSO4 (5 equivalents), sodium ascorbate (5 equivalents), and propargyl-CRBN (1 equivalent) in a THF:H2O (1:1) mixture overnight at room temperature. Upon completion, dilute the reaction mixture with ACN (1 mL) and purify by preparative HPLC.

[0274] Example

[0275] NUCC-0201202: Preparative HPLC (45-95%, 50x30, C18, 50 mL / min, Rt = 3.2-3.7 min). UVmax = 222 nm. 11H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 8.26 (s, 1H), 7.90 (s, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 7.65 - 7.43 (m, 5H), 7.37 (t, J = 7.9 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.86 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.26 (s, 2H), 5.04 - 4.79 (m, 3H), 4.32 (s, 2H), 4.08 (s, 2H), 3.84 - 3.45 (m, 13H), 3.04 - 2.51 (m, 5H), 2.23 - 1.95 (m, 4H), 1.57 (s, 4H) ppm.

[0276] NUCC - 0201203: Preparative HPLC (45 - 95% 50x30, C18, 50 mL / min, Rt = 3.25 - 4 min). UVmax = 222 nm. 1 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 8.29 (s, 1H), 7.91 (s, 3H), 7.78 (d, J = 11.5 Hz, XXXX 3H), 7.61 (t, J = 7.9 Hz, 2H), 7.52 (d, J = 8.3 Hz, 4H), 7.42 (dd, J = 14.9, 7.9 Hz, 3H), 7.14 (d, J = 8.1 Hz, 2H), 6.87 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 5.07 - 4.79 (m, 4H), 4.37 (t, J = 5.1 Hz, 2H), 4.07 (s, 3H), 3.85 - 3.32 (m, 20H), 3.01 - 2.53 (m, 5H), 2.26 - 1.93 (m, 4H), 1.58 (s, 4H) ppm.

[0277] NUCC_0201660: Preparative HPLC (45 - 95% 50x30, C18, 50 mL / min, Rt = 4.25 min). UVmax = 222 nm.

[0278] NUCC - 0201702: 1 It should be noted that in the provided text, there seems to be an "XXXX" in the 1H NMR data in line , which might be an error or an incomplete notation. If this is a real data point, it needs to be corrected for a more accurate translation.1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.5, 7.3 Hz, 1H), 7.61 - 7.37 (m, 4H), 7.17 (d, J = 8.6 Hz, 1H), 6.96 (t, J = 6.2 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.53 (s, 1H), 5.39 (d, J = 2.8 Hz, 3H), 4.89 (dd, J = 12.3, 5.4 Hz, 1H), 4.60 - 4.40 (m, 2H), 4.08 - 3.90 (m, 3H), 3.81 (d, J = 5.3 Hz, 4H), 3.69 - 3.48 (m, 7H), 3.27 (q, J = 6.8 Hz, 2H), 2.26 - 2.03 (m, 4H), 1.85 (q, J = 6.4 Hz, 2H), 1.23 (d, J = 2.2 Hz, 3H) ppm.

[0279] NUCC - 0201703: Preparative HPLC (20 - 80% 50x30, C18, 50 mL / min, Rt = 4.15 min). Uvmax = 222 nm. Cannot open NMR - fid

[0280] NUCC - 0201704: Preparative HPLC (20 - 80% 50x30, C18, 50 mL / min, Rt = 4 min). Uvmax = 222 nm. 1 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 33.9 Hz, 2H), 8.07 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 - 7.37 (m, 1H), 7.02 (d, J = 4.2 Hz, 1H), 6.88 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.28 (d, J = 3.0 Hz, 1H), 4.92 (dd, J = 11.9, 5.5 Hz, 1H), 4.40 (t, J = 5.1 Hz, 1H), 4.07 (t, J = 5.1 Hz, 1H), 3.94 (s, 1H), 3.75 (t, J = 5.1 Hz, 1H), 3.68 - 3.41 (m, 4H), 3.02 - 2.64 (m, 2H), 2.15 (s, 1H), 1.24 (s, 2H), 0.84 (d, J = 22.7 Hz, 1H) ppm.

[0281] The in vitro metabolism of NUCC-176242 and NUCC-176248 was tested using mouse liver microsomes and mouse S9 fractions. Compared with NUCC-176248, NUCC-176242 showed significant metabolism using mouse S9 fractions, which was attributed to the conjugation of S9 on the N-1 nitrogen atom of the pyrazole ring.

[0282] The pharmacokinetics of NUCC-176242 and NUCC-176248 were investigated in mice by intravenous administration of 5 mg / kg and measurement of plasma concentrations over time. The observed in vivo metabolism of NUCC-176242 and NUCC-176248 correlated well with the in vitro metabolism of NUCC-176242 and NUCC-176248 tested above.

[0283] surface

[0284] Table 1. Representative compounds

[0285] Table 2. Bioactivity of representative compounds

[0286] Table 3. Bioactivity of representative compounds a MycCap cell survival rate b Cell viability of PC12 cells c % of the remaining compounds after 60 min of treatment with mouse liver microsomes

[0287] References

[0288] [1] Huang M, Weiss WA. 2013. Neuroblastoma and MYNC. Cold Spring HarbPerspect Med 3: a014415.

[0289] [2]Roussel MF, Robinson GW. 2013. Role of MYC in medulloblastoma. Cold Spring Harb Perspect Med 3:a014308.

[0290] [3]Gabay M, Li Y, Felsher DW. 2014. MYC activation is a hall mark of cancer initiation and maintenance. Cold Spring Harb Perspect Med doi:10.1101 / cshperspect.a014241.

[0291] [4]Schmitz R, Ceribelli M et al., 2014. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med 4:a014282.

[0292] [5]Michael R. McKeown and James E. Bradner, Cold Spring Harb Perspect Med 2014;4:a014266

[0293] [6]Soucek L, Whitfield JR et al., 2013. Inhibition of MYC family protein eradicates KRas-driven lung cancer in mice. Genes Dev 27:504 - 513.

[0294] [7]S. Fletcher, E.V. Prochownik, Small-molecule inhibitors of the MYC oncoprotein, Biochim.Biophys.Acta(2014).

[0295] Example 2 - Biological Assays

[0296] Proliferation Assay( Figure 11PC3 prostate cancer cell line with high Myc levels and PC12 pheochromocytoma tumor cell line with non-functional Max protein, independent of the Myc-Max complex, were gradually isolated from ATCC. Cells were seeded at 1000 cells per well in 96-well plates, and different concentrations of the Myc inhibitor 361 were added to the cells on the second day. After 3 days of treatment, fresh medium containing 361 was added again, and cell viability was determined by MTS assay on day 5 post-treatment. (See [link to MTS assay]) Figure 11 ).

[0297] Myc Ebox luciferase reporting assay Figure 12 MycCap cells stably expressing luciferase with the CMV promoter (MycCap-luc) or the c-Myc E-box-luciferase reporter molecule (MycCap Ebox-luc) were seeded at 10,000 cells per well in 96-well white plates. Serial dilutions of 361 were applied the next day. After 4 hours of treatment, luminescence signals were measured immediately after adding 150 μg / ml luciferin to the wells. (See...) Figure 12 ).

[0298] Cell thermal migration assay (CETSA) Figure 13 PC3 cells with 70% to 80% confluence in 15 cm culture dishes were treated with 6 μM 361 or DMSO for 30 min. Cells were harvested and washed once with PBS, then resuspended in 1 mL of PBS supplemented with protease and phosphatase inhibitors. Therefore, in this step, the PBS contained 6 μM 361 or DMSO accordingly. The cell suspension was dispensed into 7 to 10 100 μl 0.2 mL PCR tubes (approximately 1 million cells), and each tube was assigned a temperature point. The samples were heated at the specified temperature for 2 min in an AB 96-well thermal cycler. Immediately after heating, the tubes were removed and incubated at room temperature for 3 min. After this 3 min incubation, the tubes were immediately flash-frozen in liquid nitrogen and stored at -80°C. To lyse the cells, three freeze-thaw cycles were performed in LN. After each thawing, the tubes were briefly vortexed. Cell lysates were collected and centrifuged at 20,000 g for 20 min at 4 °C to remove cell debris, as well as precipitated and aggregated proteins. After adding loading buffer, the cell lysates were boiled at 90 °C for 5 min and prepared for Western blot analysis. The c-Myc antibody was derived from Abcam (Ab32072). Data were generated from three independent experiments, and c-Myc protein intensity was quantified using Image1. (See [link to image]) Figure 13 ).

[0299] Gene expression profiling analysis Figure 14PC3 cells were treated with 10 μM Min9-S1 for 24 hours. mRNA was extracted using the RNAeasyPlus mini kit (Qiagen, catalog number 74134). Gene expression profiles were analyzed using HTA 2.0 from Affymetrix. GSEA of four Myc-dependent gene marker groups in the transcriptome of PC3 cells treated with Min9-S1 or the mediator (VEH) (Zeller et al., 2003; Schuchmacher et al., 2001; Kim et al., 2006; Schlosser et al., 2005) showed a strong association with downregulation of expression in Min9-S1 treatment. The repressed genomes in Min9-S1-treated PC3 cells are listed in the table, including the number of genes (n) in each group, the calibrated enrichment score (NES), and the statistical significance test (FDR q value). (See also: [link to table]) Figure 14 ).

[0300] MycCap FVB allogeneic graft model ( Figure 15 FVB mice were subcutaneously inoculated on both sides with 100 μL of 1 x 10⁻⁶ styrene in a matrix gel. 6 MycCap cells. When the tumor size reaches 150mm. 3 When the average size of the tumor was determined, mice were randomly assigned to two groups based on tumor volume. Mice were administered 50 mg / kg of 361 or its carrier (Veh) intraperitoneally twice daily for two days. Treatment was paused for 10 days, and then started at a lower dose of 70 mg / kg daily for another 9 days. Tumor size was measured twice weekly during the experiment. (See [link to study]) Figure 15 ).

[0301] The combination of Myc inhibitor 361 and immunotherapy ( Figure 16 The MycCap FVB allogeneic transplantation model was treated with 361 (50 mg / kg) for 2 days, followed by treatment with anti-PD-1 antibody for 2 days (100 μg / day), and this 4-day treatment cycle was maintained for 4 cycles. (See...) Figure 16 ).

[0302] Combination therapy of Myc inhibitors and Ara-C in AML xenograft models ( Figure 17 ). Use 5 x 10 ppm suspended in PBS and matrix gel (1:1) 6 MV411 cells were inoculated into CB17 SCID mice at a high density. Tumors reached ~200 to 500 mm in size. 3 Mice were then randomly assigned to six different groups based on tumor volume. Mice were treated alone with the mediators NU031, NU975, or in combination with cytarabine (Ara-C). The combination treatments showed significant differences compared to the control group. (See...) Figure 17 ).

[0303] NCI60 Distribution - NCI 60 Cell Dosage Screening

[0304] General Description. As of early 2007, all compounds submitted to the NCI 60 cell screening were initially tested at a single high dose (10⁻⁵ M) across the entire NCI 60 cell group. Only compounds meeting predetermined threshold inhibition criteria in a minimum number of cell lines were eligible for the full 5-dose assay. Threshold inhibition criteria for inclusion in the 5-dose screening were selected based on careful analysis of historical DTP screening data to effectively capture compounds with antiproliferative activity. Threshold criteria may be updated as other available data become available.

[0305] Interpretation of One-Dose Data. One-dose data are reported as an average percentage of cell growth and superficially resemble the average of a 5-dose assay. The numbers reported for one-dose assays are growth relative to a no-drug control and to a time value of zero. This allows for the detection of both growth inhibition (values ​​between 0 and 100) and lethality (values ​​less than 0). This is the same as the 5-dose assay described below. For example, a value of 100 indicates no growth inhibition. A value of 40 would mean a 60% growth inhibition rate. A value of 0 indicates no net growth during the experiment. A value of -40 means a 40% lethality rate. A value of -100 indicates that all cells have died. Information from the one-dose average chart can be used for comparative analysis.

[0306] NCI 60 cell screening with 5 doses ( Figure 18 , Figure 19 and Figure 20 A compound that showed significant growth inhibition in dose screening was evaluated in a 60-cell group at five dose levels.

[0307] Human tumor cell lines for the cancer screening panel were grown in RPMI 1640 medium containing 5% fetal bovine serum and 2 mM L-glutamine. For typical screening experiments, cells were seeded into 100 μL of 96-well microtiter plates at a density of 5,000 to 40,000 cells / well, depending on the doubling time of individual cell lines. After seeding, the microtiter plates were incubated for 24 h at 37°C, 5% CO2, 95% air, and 100% relative humidity before the addition of experimental drugs.

[0308] After 24 h, two plates of each cell line were fixed in situ with TCA to represent the measurement of the cell population of each cell line at the time of addition of the drug (Tz). The experimental drug was dissolved in dimethyl sulfoxide at 400 times the desired final maximum test concentration and stored frozen until use. At the time of addition of the drug, aliquots of the frozen concentrate were thawed and diluted in complete medium containing 50 μg / ml gentamicin to twice the desired final maximum test concentration. Four additional, 10-fold or 1 / 2log serial dilutions were performed to obtain a total of five drug concentrations plus control. Aliquots of 100 μl of these different drug dilutions were added to appropriate microtiter wells that already contained 100 μl of medium to achieve the desired final drug concentration.

[0309] After addition of the drug, the plates were incubated for an additional 48 h at 37 °C, 5% CO2, 95% air and 100% relative humidity. For adherent cells, the assay was terminated by addition of cold TCA. The cells were fixed in situ by addition of 50 μl of cold 50% (w / v) TCA (final concentration, 10% TCA) and incubated at 4 °C for 60 min. The supernatant was discarded and the plates were washed five times with tap water and air dried. A solution of 0.4% (w / v) sulforhodamine B (SRB) in 1% acetic acid (100 μl) was added to each well and the plates were incubated at room temperature for 1 min. After staining, the unbound dye was removed by washing five times with 1% acetic acid and the plates were air dried. Subsequently, the bound stain was solubilized with 10 mM Tris base and the absorbance was read at a wavelength of 515 nm on an automated plate reader. For suspension cells, the method was the same, except that the assay was terminated by fixing the sedimented cells to the bottom of the wells by addition of 50 μl of 80% TCA (final concentration, 16% TCA). Using seven absorbance measurements [time zero (Tz), control growth (C) and test growth (Ti) at five concentration levels of the drug], the percentage growth at each drug concentration level was calculated. The percentage growth inhibition was calculated as follows:

[0310] For concentrations where Ti> / =Tz, [(Ti - Tz) / (C - Tz)] x 100

[0311] For concentrations where Ti < Tz, [(Ti - Tz) / Tz] x 100

[0312] For each experimental reagent, three dose-response parameters were calculated. The 50% growth inhibition (GI50) was calculated based on [(Ti-Tz) / (C-Tz)] x 100 = 50, which is the drug concentration (e.g., as determined by SRB staining) that results in a 50% reduction in net protein increase in control cells during drug incubation. The drug concentration that results in total growth inhibition (TGI) was calculated based on Ti = Tz. The LC50 (the drug concentration that results in a 50% reduction in protein measured at the end of treatment compared to the beginning) was calculated based on [(Ti-Tz) / Tz] x 100 = -50, representing the net cell loss after treatment. If the activity level was reached, a value was calculated for each of these three parameters; however, if the effect was not reached or exceeded, the value of the parameter was expressed as greater than or less than the maximum or minimum concentration tested. Results are as follows: Figure 18 , Figure 19 and Figure 20 As shown in the image.

[0313] In the foregoing description, it will be apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention exemplarily described herein can be suitably practiced without any or more elements, or one or more limitations, not specifically disclosed herein. The terms and expressions used are descriptive and not restrictive, and are not intended to exclude any equivalent forms of the features shown and described or portions thereof when using such terms and expressions, but rather to recognize that various modifications can be made within the scope of the invention. Therefore, it should be understood that although the invention has been exemplified by specific embodiments and optional features, modifications and / or alterations can be made to the concepts disclosed herein by those skilled in the art, and such modifications and alterations are considered to be within the scope of the invention.

[0314] This document may cite numerous patent and non-patent references. All cited references are incorporated herein by reference in their entirety. If there is any inconsistency between the definition of a term in this specification and the definition of a term in a cited reference, the definition in this specification shall prevail.

Claims

1. Compounds having formula I: in R 1 It is hydrogen, or R 1 It is aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 1 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 2 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 3 It can be hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, benzyl, hydroxyl, halogen, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, or R 4 It is aryl or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl (e.g., phenyl), hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy; R 5 It is an alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl or halogen; R 6 It is hydrogen, amino, alkyl, or R 6 It is aryl or benzyl; R 6 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy; or R 6 and R 5 Together they form a pattern The ring structure; R 7 It is hydrogen or halogen, or R 7 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 7 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; The condition is R 4 and R 6 At least one of them is hydrogen; The condition is if R 5 If it is hydrogen, then p is 1 and m is 1; and The condition is if R 1 (CH2) n (X) p - is hydrogen, hydroxyl or alkyl, and R 5 If it is a hydroxyl group, then m is 1, or R 2 and R 3 At least one of them is not hydrogen.

2. The compound of claim 1, wherein R 2 and R 7 At least one of them is aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, and R 2 and R 7 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

3. The compound of claim 1, wherein m is 0 and R 2 It is hydrogen; or R is one of them. 7 It is hydrogen.

4. The compound of claim 1, wherein R 2 It is aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, and R 2 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl; and wherein R 7 It is hydrogen.

5. The compound of claim 1, wherein m is 0 and R 2 It is hydrogen; and R is in this case. 7 It is aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, and R 7 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, and alkoxycarbonyl.

6. The compound of claim 1, having formula I(i) or I(ii):

7. The compound of claim 1, having the formula selected from Ia(i), Ia(ii), Ib(i), Ib(ii), Ic(i) and Ic(ii):

8. Compounds having formula II: in Y is either C or N; R 1 It is hydrogen or aryl, benzyl, heteroaryl, cycloalkyl or cyclohexaalkyl, optionally R 1 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 2 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 3 It can be hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, benzyl, hydroxyl, halogen, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, aryl, or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy; R 5 It can be alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, or halogen; R 6 It is hydrogen, amino, alkyl, aryl, or benzyl; R 6 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy; and R 7 It is hydrogen or halogen, or R 7 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 7 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl.

9. The compound of claim 4, having formula IIa:

10. Compounds having Formula III: in: R 1 It is hydrogen or aryl, benzyl, heteroaryl, cycloalkyl or cyclohexaalkyl, optionally R 1 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 2 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, aryl, or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy; R 5 It is an alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, and halogen; and R 7 It is hydrogen or halogen, or R 7 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 7 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl.

11. The compound of claim 10, having formula IIIa or IIIb:

12. Compounds having formula IV: in: R 1 It is hydrogen or aryl, benzyl, heteroaryl, cycloalkyl or cyclohexaalkyl, optionally R 1 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; Y is either C or N; Z is C or N; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 2 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 4 It is hydrogen, amino, alkyl, aryl, or benzyl; R 4 Optionally substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy; R 5 It is an alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, and halogen; and R 7 It is hydrogen or halogen, or R 7 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 7 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl.

13. Compounds having formula V: in: R 1 It is hydrogen or aryl, benzyl, heteroaryl, cycloalkyl or cyclohexaalkyl, optionally R 1 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; n is 0, 1, or 2; p is 0 or 1; X is O or NH, or R 1 (CH2) n (X) p - is an N-piperazinyl group optionally substituted with an alkyl N-; m is 0 or 1; R 2 It is hydrogen or halogen, or R 2 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 2 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl; R 5 It is an alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, and halogen; and R 7 It is hydrogen or halogen, or R 7 It is alkyl, aryl, benzyl, heteroaryl, cycloalkyl, or cyclohexaalkyl, optionally R 7 It is substituted at one or more positions by one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, halogen, cyano, amide, hydrazone, carbonyl, carboxyl and alkoxycarbonyl.

14. A pharmaceutical composition comprising the compound of claim 1 and a suitable pharmaceutical carrier, excipient or diluent.

15. A method of treating cancer, comprising administering the composition of claim 14 to a patient suffering from cancer.

16. A pharmaceutical composition comprising the compound of claim 8 and a suitable pharmaceutical carrier, excipient or diluent.

17. A method of treating cancer, comprising administering the composition of claim 16 to a patient suffering from cancer.

18. A pharmaceutical composition comprising the compound of claim 10 and a suitable pharmaceutical carrier, excipient or diluent.

19. A method of treating cancer, comprising administering the composition of claim 18 to a patient suffering from cancer.

20. A pharmaceutical composition comprising the compound of claim 12 and a suitable pharmaceutical carrier, excipient or diluent.

21. A method of treating cancer, comprising administering the composition of claim 20 to a patient suffering from cancer.

22. A pharmaceutical composition comprising the compound of claim 13 and a suitable pharmaceutical carrier, excipient or diluent.

23. A method of treating cancer, comprising administering the composition of claim 22 to a patient suffering from cancer.

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